Furan or thiophene derivative and medicinal use thereof

ABSTRACT

The present invention provides a compound represented by the formula (I): 
                         
[wherein R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, p is 0, 1 or 2, and when p is 2, each R may be the same or different, R 1  is a hydrogen atom or an optionally substituted hydrocarbon group, R 2  is an optionally substituted aromatic group, Ring A is an optionally substituted monocyclic aromatic ring or optionally substituted bicyclic aromatic fused ring, X 1  is an oxygen atom or a sulfur atom, X 2  is a bond, an oxygen atom or —S(O) n — (wherein n is 0, 1 or 2), Y is a bond, an oxygen atom, —S(O) m —, —C(═O)—N(R 3 )— or —N(R 3 )—C(═O)— (R 3  is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m is 0, 1 or 2), M 1 , M 2  and M 3  may be the same or different and are each independently a bond or an optionally substituted divalent aliphatic hydrocarbon group, and M 4  is an optionally substituted divalent aliphatic hydrocarbon group] or a salt thereof, which is useful as a prophylactic and/or therapeutic agent for lipid metabolism abnormality, arteriosclerotic disease and sequelae thereof, diabetes mellitus and the like.

This application is the National Phase filing of International PatentApplication No. PCT/JP03/11308, filed Sep. 4, 2003.

TECHNICAL FIELD

The present invention relates to a novel furan or thiophene derivativewhich has excellent blood lipid metabolism ameliorating action and bloodglucose lowering action, and is useful as a prophylactic and/ortherapeutic agent for lipid metabolism abnormality, arterioscleroticdisease and sequelae thereof (for example, ischemic cardiac disease,cerebral disease or peripheral arterial occlusion and the like),diabetes mellitus, impaired glucose tolerance and the like.

BACKGROUND ART

Peroxisome proliferator activated receptor (PPAR) is a receptor whichwas cloned in 1990 as a protein mediating actions of increasingperoxisome that is an intracellular small organ associated withlipolysis (Nature, vol. 347, p. 645 (1990)), and a transcription factorthat belongs to a nuclear receptor having a ligand such as estrogen,thyroid hormone, fat-soluble vitamin, etc. Three isoforms of PPARα,PPARδ and PPARγ have been identified so far. It is known that PPARα ismainly expressed in the liver, heart, kidney, adrenal, digestive tractand skeletal muscle and PPARγ in immune systemic organs, largeintestine, small intestine, adrenal and adipocytes, and PPARδ isubiquitarily expressed with no specificity for tissues. Any PPAR forms astable hetero dimer with retinoid X receptor (RXR) and binds to aspecific DNA recognizing sequence of the target gene (PPRE) to controlit.

PPARα agonist increases lipoprotein lipase (EMBO Journal, vol. 15, p.5336 (1996)) and suppresses expression of apoC-III (Journal of ClinicalInvestigation, vol. 95, p. 705 (1995)) to promote catabolism oftriglyceride-rich lipoprotein. Furthermore, a fatty acid transportprotein and a binding protein specific for each tissue of liver, muscle,fat, small intestine and the like are induced (Journal of BiologicalChemistry, vol. 273, p. 16710 (1998)), to promote uptake of free fattyacid. Furthermore, it strongly increases fatty acid β oxidase localizedin the mitochondria and peroxisome (Journal of Biological Chemistry,vol. 273, p. 5678 (1998)). Furthermore, PPARα is reported to regulatepositively apoA-I gene in human (Journal of Biological Chemistry, vol.269, p. 31012 (1994)). As the results, PPARα agonist promotes loss oftriglyceride from the blood, decreases triglyceride synthesis andultra-low-density lipoprotein secretion to decrease serum triglyceride,and increases blood high-density lipoprotein, to ameliorate blood lipidcomposition. For PPARα agonist, a lipid lowering agent known as fibratetype drugs has been already clinically used, and it is clear that PPARαagonist is useful as a prophylactic and/or therapeutic agent forhyperlipidemia and the like. Furthermore, PPARα agonist is known to havephysiological actions induce UCP2 (uncoupling protein-2) which is one ofuncoupling proteins inhibiting oxidative phosphorylation which is thelast step of ATP production system in the liver and small intestine(Biochemical and Biophysical Research Communications, vol. 257, p. 879(1999), and Biochimica et Biophysica Acta, vol. 1530, p. 15 (2001)), andalso known to induce UCP-3 (uncoupling protein-3) in skeletal muscle(FASEB Journal, vol. 15, p. 833 (2001)). From these facts, it isexpected to have anti-obesity action by increase of energy consumptionor insulin resistance ameliorating action (Diabetes, vol. 50, p. 411(2001)). Furthermore, it is reported that PPARα is expressed in humanaortic smooth muscle cells, that PPARα agonist suppresses IL-6 inductionby the stimulation of IL-1β (Nature, vol. 393, p. 790 (1998)), and thatPPARα agonist suppresses VCAM-1 expression of endothelial cells by TNF-αor IL-1β (Circulation, vol. 99, p. 3125 (1999)), which suggests that itsuppresses formation of atherosclerosis involving inflammatory process.Furthermore, PPARα agonist is found to increase expression of SR-BI(scavenger receptor B class I) and ABCA1 (ATP binding cassettetransporter A1) (Circulation, vol. 101, p. 2411 (2000), and NatureMedicine, vol. 7, p. 53 (2001)), which suggests that it increasescholesterol reverse transport system to act against arteriosclerosis.Furthermore, from the fact that potentiation of ABCA1 expression in thesmall intestine promotes enteral excretion of free cholesterol (Journalof Clinical Investigation, vol. 108, p. 303 (2001)), PPARα agonist isexpected to also have serum cholesterol lowering action. On the otherhand, PPARα agonist is reported to reduce fibrinogen serum level in mice(Blood, vol. 93, p. 2991 (1999)), which suggests possibility ofsuppressing cardiovascular event following plaque formation bysuppression of thrombus formation.

Endogenous ligand candidates of PPARδ (also referred to as PPARβ or NUCIfor human) includes long chain fatty acid and carbaprostacyclin. PPARδis universally expressed, especially intensively in intestines, kidneyand heart. It is reported that PPARδ selective agonist promotes exportof cholesterol dependently on apoA-I in macrophage, fibroblast andenteral cells, increases blood high-density lipoprotein and decreaseslow-density lipoprotein, fast triglyceride and fast insulin in obesityRhesus monkey (Proceedings of the National Academy of Sciences of theUnited States of America, vol. 98, p. 5306 (2001)), and shows an actionof increasing HDL-C in db/db mouse (FEBS letters, vol. 473, p. 333(2000)). Therefore, PPARδ agonist is considered to be able to be a bloodlipid composition ameliorating agent, and is likely to be an agent ofsuppressing or treating arteriosclerotic progress, and further an agentof preventing attack of ischemic cardiac disease and the like byreducing syndrome X risk factor. Furthermore, PPARδ agonist is known toinduce differentiation and proliferation of glia cells (Molecular andCellular Biology, vol. 20, p. 5119 (2000) and Glia, vol. 33, p. 191(2001)). Furthermore, PPARδ agonist is reported to show an action ofpromoting differentiation of mouse precursor adipocytes (Journal ofBiological Chemistry, vol. 274, p. 21920 (1999); Journal of BiologicalChemistry, vol. 275, p. 38768 (2000); Journal of Biological Chemistry,vol. 276, p. 3175 (2001)); an action of promoting expression of UCP-2and UCP-3 of skeletal muscle cells in rat and human (Journal ofBiological Chemistry, 2001, 276, p. 10853 and Endocrinology, vol. 142,p. 4189 (2001)); and an action of inhibiting adrenal medulla cell deathby hyperosmolar stress (Journal of Biological Chemistry, vol. 277, p.21341 (2002)). Furthermore, PPARδ is reported to be involved in coloncancer (Cell, vol. 99, p. 335 (1999) and Proceedings of the NationalAcademy of Sciences of the United States of America, vol. 98, p. 2598(2001)), implantation in pregnancy (Genes and Development, vol. 13, p.1561 (1999)), bone resorption action in osteoclasts (Journal ofBiological Chemistry, vol. 275, p. 8126 (2000)), apoptosis ininflammation (Genes and Development., vol. 15, p. 3263 (2001)), andcontrol of type II acyl-CoA synthase in brain (Journal of BiologicalChemistry, vol. 274, p. 35881 (1999)). Also, for PPARδ agonist, use as aprophylactic and/or therapeutic agent for atherosclerosis is disclosedin the pamphlet of WO92/10468, and use as a therapeutic agent fordiabetes mellitus or an anti-obesity agent is disclosed in the pamphletof WO97/28115.

PPARγ is induced to be expressed in the very beginning of adipocytedifferentiation, and plays important roles in adipocyte differentiationas master regulator. In recent years, it is suggested that15-deoxy-Δ^(12, 14) prostaglandin J2, which is a metabolite ofprostaglandin D2, is an endogenous ligand of PPARγ, and it has beenclarified that certain insulin sensitizers represented bythiazolidinedione derivatives have a PPARγ ligand activity and thestrength of the activity parallels with a hypoglycemic action oradipocyte differentiation promoting action [Cell, vol. 83, p. 803(1995); Journal of Biological Chemistry, vol. 270, p. 12953, (1995);Journal of Medicinal Chemistry, vol. 39, p. 655 (1996)]. More recently,it has been elucidated that 1) PPARγ is expressed in the cultured cellderived from human liposarcoma and the addition of PPARγ ligand stopsits growth [Proceedings of The National Academy of Sciences of TheUnited States of America, vol. 94, p. 237 (1997)], 2) nonsteroidalanti-inflammatory drugs represented by indomethacin and phenoprofen havea PPARγ ligand activity [Journal of Biological Chemistry, vol. 272, p.3406 (1997)], 3) PPARγ is highly expressed in activated macrophage, andthe addition of its ligand leads to the inhibition of the transcriptionof the gene involved in inflammation [Nature, vol. 391, p. 79 (1998)],4) PPARγ ligand inhibits production of inflammatory cytokines (TNFα,IL-1β, IL-6) by monocyte [Nature, vol. 391, p. 82 (1998)] and the like.

Agents of binding to PPAR receptor are disclosed, for example, in thepamphlet of WO00/64876, the pamphlet of WO02/144291, the pamphlet ofWO01/79197, the pamphlet of WO00/23442, the pamphlet of WO99/46232,JP-A-2001-261612, the pamphlet of WO01/92201, the pamphlet of WO0/75103,the pamphlet of WO01/60807, the specification of US-A-2002/0037911, thespecification of U.S. Pat. No. 6,369,055, the specification ofUS-A-2002/0022656, the pamphlet of WO97/28149, the specification ofUS-A-2002/0042441, the pamphlet of WO01/00603, the pamphlet ofWO02/18355, the pamphlet of WO02/16331, the pamphlet of WO02/16332, thepamphlet of WO01/16120, the pamphlet of WO97/36579 and the like.

Recently, it has been shown that by the action of free fatty acid on Gprotein-coupled receptor GPR40 which is expressed in pancreas, insulinsecretion from pancreatic β cell is promoted (Nature (advance onlinepublication), Feb. 23, 2003, doi:10.1038/nature01478).

On the other hand, compounds having a furan or thiophene structure areknown as those described in the following documents and the like.

The pamphlet of WO00/23442 has described a compound as an agent ofbinding to PPAR ligand receptor represented by the formula:

[wherein R²¹ groups are each independently a hydrogen atom, C1-8 alkyl,a halogen atom, C1-4 alkoxy, C1-4 alkylthio, nitro, NR²⁴R²⁵ (wherein R²⁴and R²⁵ are each independently C1-4 alkyl.), cyano, trifluoromethyl,trifluoromethyloxy, carbocycle or heterocycle (the carbocycle andheterocycle may be substituted with a group selected from C1-4 alkyl,C1-4 alkoxy, a halogen atom or trifluoromethyl.), R²² is a hydrogenatom, C1-8 alkyl, a halogen atom, C1-4 alkoxy, C1-4 alkylthio, nitro,NR²⁴R²⁵ (wherein R²⁴ and R²⁵ are each independently C1-4 alkyl.), cyano,trifluoromethyl or trifluoromethyloxy,

-   R²³ is a hydrogen atom or C1-4 alkyl,-   X²¹ is —N— or —CH—,-   X²² and Y²⁰ are each independently —O—, —S— or —NR²⁶— (wherein-   R²⁶ is a hydrogen atom or C1-4 alkyl.),-   Z²⁰ is —O— or —S(O)_(p)′— (wherein p′ is 0, 1 or 2.),-   R²⁷ and R²⁸ are each independently a hydrogen atom or C1-4 alkyl, or    C3-7 cycloalkylene with the carbon atom to which they are attached,

is carbocycle or heterocycle,

is a double a bond or a triple bond, and

-   q and r are each independently 1 to 3.],-   a non-toxic salt and a hydrate thereof.

JP-A-1989-143856 has disclosed a compound as an anti-allergic andanti-inflammatory agent represented by the formula:

[wherein X³⁰ is —C(R³⁴)═ or —N═,

-   Y³⁰ is —C(R³⁴)═N—, —N═C(R³⁴)—, —C(R³⁴)═C(R³⁴)—, —O—, —S— or    —N(R³⁴)—,-   Z³⁰ is —(CH₂)n′O—, —(CH₂)n′-S—, —(CH₂)n′-N(R³⁴)—, —C(═O)—N(R³⁴)—,    —(CH₂)n′S(O)—, —(CH₂)n′SO₂—, —C(R³⁴)═C(R³⁴)— or —C═C—,-   R³¹ is —(CHR³⁷)_(n)COOR³³,-   n′ is each independently 0 to 5,-   R³² is each independently hydrogen, lower alkyl, lower alkoxy, lower    alkoxycarbonyl, trifluoromethyl, nitro, cyano or halogen,-   R³³ is

-   W is a bond or —O—, —S—, —N(R³⁴)—,-   m′ is 1 to 15,-   R³⁴ is each independently hydrogen or lower alkyl, and-   R³⁷ is hydrogen or methyl] (the definitions in the formula are    excerpted for necessary part), and a pharmaceutically acceptable    salt thereof.

PCT Japanese Translation Patent Application Publication No. 1993-507920has described that a compound represented by the formula:

[wherein A^(c) is

nC is 0 or 1;

-   is a bond or not;-   R^(c) is C1-C8 alkyl, C3-C7 cycloalkyl, C3-C8 alkenyl, C3-C8    alkynylphenyl, C7-C8 phenylalkyl, C2-C8 alkanoyl, or, C1-C3 alkyl,    trifluoromethyl, hydroxy, C1-C3 alkoxy, or one of the    above-mentioned groups mono- or di-substituted with fluorine or    chlorine;-   X^(c) is S, O, NR^(2c), —CH═CH—, —CH═N— or —N═CH—;-   R^(2c) is hydrogen, C1-C3 alkyl, phenyl or benzyl;-   Y^(c) is CH or N;-   Z^(c) is hydrogen, C1-C7 alkyl, C3-C7 cycloalkyl, phenyl, or C1-C 3    alkyl, trifluoromethyl, C1-C3 alkoxy, phenyl, phenoxy, benzyl,    benzyloxy, phenyl mono- or di-substituted with fluorine or chlorine;-   X′^(c) is O, S, SO or SO₂;-   Y′^(c) is hydroxy, C1-C3 alkoxy and the like; and-   Z′^(c) is hydrogen or C1-C3 alkyl] has hypoglycemic action and blood    lipid lowering action.

The pamphlet of WO01/93840 has described compounds represented by theformula:

as an integrin receptor ligand.

The pamphlet of WO01/10847 has described a compound represented by theformulae:

as an integrin receptor ligand.

The pamphlet of WO01/23357 has described a compound represented by theformula:

as an integrin receptor ligand.

The pamphlet of WO01/87038 has described a compound represented by theformula:

as a phosphodiesterase inhibitor.

The pamphlet of WO99/6393 has described a compound represented by theformula:

as an anticancer agent or metastasis suppresser.

JP-A-1997-221476 has described a compound represented by the formulae:

as starting materials of the compound having affinity for vasopressinreceptor.

Journal of Medicinal Chemistry, vol. 39, p. 3636 (1996) has described acompound represented by the formula:

as a secretory phospholipase A₂ inhibitor.

The pamphlet of WO01/53267 has described a compound represented by theformula:

as a starting material of thrombopoietin receptor agonist.

The pamphlet of WO99/19300 has described a compound represented by theformula:

as a prostaglandin agonist.

CHEMCATS [online] has disclosed compounds represented by the formulae:

As a PPAR agonist, the pamphlet of WO02/092590 has described a furanderivative, the pamphlet of WO02/083616 has described a thiophenederivative, and the pamphlet of WO02/096893, the pamphlet of WO02/096894and the pamphlet of WO02/096895 have described a thiazole derivative.

DISCLOSURE OF INVENTION

It is desired to develop a novel compound which is useful as aprophylactic and/or therapeutic agent for PPAR-related diseases (forexample, lipid metabolism abnormality, arteriosclerotic disease andsequelae thereof (for example, ischemic cardiac disease, cerebraldisease or peripheral arterial occlusion and the like), diabetesmellitus, impaired glucose tolerance and the like), and, has excellentproperties such as little side-effects and the like as a pharmaceutical.

Furthermore, a non-peptide low molecular agonist or antagonist for GPR40receptor has not been known so far, and it is desired to develop a novelcompound which has an action of regulating GPR40 receptor functions andis useful as an insulin secretion enhancer or a prophylactic and/ortherapeutic agent for diabetes mellitus and the like.

The present inventors have made extensive study under abovecircumstances, and firstly synthesized a furan derivative and athiophene derivative having the following particular structure, andfound unexpectedly that such compound exerts excellent preventing andtreating action for PPAR-related conditions or diseases by regulatingPPAR, and exerts excellent preventing and treating action for GPR40receptor-associated conditions or diseases by excellent GPR40 receptoragonist activity. Based on these findings, the present inventors havereached completion of the present invention.

That is, the present invention relates to:

(1) A compound represented by the formula (I):

[wherein R is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, p is 0, 1 or 2, and when p is2, each R may be the same or different, R¹ is a hydrogen atom or anoptionally substituted hydrocarbon group, R² is an optionallysubstituted aromatic group, Ring A is an optionally substitutedmonocyclic aromatic ring or optionally substituted bicyclic aromaticfused ring, X¹ is an oxygen atom or a sulfur atom, X² is a bond, anoxygen atom or —S(O)_(n)— (wherein n is 0, 1 or 2), Y is a bond, anoxygen atom, —S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)— (R³ is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and m is 0, 1 or 2), M¹, M²and M³ may be the same or different and are each independently a bond oran optionally substituted divalent aliphatic hydrocarbon group, and M⁴is an optionally substituted divalent aliphatic hydrocarbon group(provided that (1) when Y is an oxygen atom or —S(O)_(m)—, M¹ is not abond, (2) when Y is a bond and one of M¹ and M² is a bond, the other ofM¹ and M² is neither a bond nor methylene, and (3) it does not include3-[3-[[(2-methyl-5-phenyl-3-furanyl)carbonyl]amino]phenyl]-2-propenoicacid, 4-[[(2-methyl-5-phenyl-3-furanyl)carbonyl]amino]benzeneaceticacid,5-[[4-[(1Z)-2-carboxy-2-chloroethenyl]benzoyl]amino]-3-phenyl-2-thiophenecarboxylicacid,3-[3-[[(2-methyl-5-phenyl-3-furanyl)carbonyl]amino]phenyl]-2-propenoicacid and 4-[[(2-methyl-5-phenyl-3-furanyl)carbonyl]amino]benzeneaceticacid)] or a pharmacologically acceptable salt thereof;

(2) The compound as described in the above-mentioned (1), wherein R isan optionally substituted alkyl, an optionally substituted aralkyl, anoptionally substituted cycloalkyl or an optionally substituted aryl;

(3) The compound as described in the above-mentioned (1), wherein p is1;

(4) The compound as described in the above-mentioned (1), wherein R¹ isa hydrogen atom;

(5) The compound as described in the above-mentioned (1), wherein R² isan optionally substituted phenyl;

(6) The compound as described in the above-mentioned (1), wherein Ring Ais an optionally substituted monocyclic aromatic ring;

(7) The compound as described in the above-mentioned (6), wherein themonocyclic aromatic ring is a monocyclic aromatic heterocycle;

(8) The compound as described in the above-mentioned (6), wherein themonocyclic aromatic ring is a benzene ring or a thiazole ring;

(9) The compound as described in the above-mentioned (1), wherein theformula:

is the formula:

(wherein Ring A′ is an optionally further substituted benzene ring);

(10) The compound as described in the above-mentioned (1), wherein X¹ isan oxygen atom;

(11) The compound as described in the above-mentioned (1), wherein X² isa bond, an oxygen atom or a sulfur atom;

(12) The compound as described in the above-mentioned (1), wherein Y isan oxygen atom or a sulfur atom;

(13) The compound as described in the above-mentioned (1), wherein Y is—C(═O)—N(R³)— (R³ is a hydrogen atom, an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andthe carbon atom is bonded to M¹, and the nitrogen atom to M²);

(14) The compound as described in the above-mentioned (13), wherein R³is a hydrogen atom, an optionally substituted alkyl, an optionallysubstituted aralkyl, an optionally substituted cycloalkyl or anoptionally substituted aryl;

(15) The compound as described in the above-mentioned (1), wherein M¹ isan alkylene having 3 or more carbon atoms;

(16) The compound as described in the above-mentioned (1), wherein M¹,M² and M³ may be the same or different and are each independently abond, an alkylene, an alkenylene or an alkynylene, and M⁴ is analkylene, an alkenylene or an alkynylene;

(17) The compound as described in the above-mentioned (1), wherein x² isan oxygen atom or —S(O)_(n)— (wherein n is 0, 1 or 2) and M³ is anoptionally substituted divalent aliphatic hydrocarbon group;

(18) The compound as described in the above-mentioned (1), wherein theformula (I) is

(wherein each of the symbols is as defined in the above-mentioned (1));

(19) The compound as described in the above-mentioned (18), wherein theformula (I′) is

(wherein the symbols are as defined in the above-mentioned (1) and (9));

(20) The compound as described in the above-mentioned (19), wherein X¹is an oxygen atom, X² is an oxygen atom or —S(O)_(n)— (wherein n is 0, 1or 2), Y is an oxygen atom, M¹ is an optionally substituted C₁₋₃alkylene, M² is a bond, M³ is a bond or an optionally substitutedmethylene, and M⁴ is an optionally substituted methylene;

(21) The compound as described in the above-mentioned (20), wherein M¹and M³ may be the same or different and are each independently anoptionally substituted methylene;

(22) The compound as described in the above-mentioned (19), wherein X¹is an oxygen atom, X² is a bond, Y is an oxygen atom, M¹ is anoptionally substituted n-propylene, M² and M³ are a bond, and M⁴ is anoptionally substituted methylene;

(23) The compound as described in the above-mentioned (18), wherein RingA is an optionally substituted monocyclic aromatic heterocycle;

(24) The compound as described in the above-mentioned (18), wherein RingA is an optionally substituted thiazole ring or an optionallysubstituted oxazole ring, X¹ is an oxygen atom, X² is a bond, Y is anoxygen atom or —S(O)_(n)—(wherein n is 0, 1 or 2), M¹ is an optionallysubstituted C₁₋₃ alkylene, M² and M³ are a bond, and M⁴ is an optionallysubstituted methylene;

(25) The compound as described in the above-mentioned (18), wherein RingA is an optionally substituted thiazole ring, X¹ is an oxygen atom, X²is a bond, Y is —S—, M¹ is an optionally substituted methylene or anoptionally substituted n-propylene, M² and M³ are a bond, and M⁴ is anoptionally substituted methylene;

(26) The compound as described in the above-mentioned (18), wherein theformula (I′) is

(wherein M¹′ is an alkylene group having 3 or more carbon atoms, and theother symbols are as defined in the above-mentioned (1) and (9));

(27) The compound as described in the above-mentioned (1), wherein R isan optionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1,R¹ is a hydrogen atom, R² is an optionally substituted phenyl group,Ring A is an optionally substituted benzene ring or an optionallysubstituted thiazole ring, X¹ is an oxygen atom, X² is a bond or anoxygen atom, Y is an oxygen atom or —C(═O)—N(R³)— (wherein R³ is ahydrogen atom, alkyl or aralkyl, and the carbon atom is bonded to M¹,and the nitrogen atom to M²), M¹, M and M³ may be the same or differentand are each independently a bond or alkylene, and M⁴ is alkylene;

(28) The compound as described in the above-mentioned (1), wherein R isan optionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1,R¹ is a hydrogen atom, R² is an optionally substituted phenyl group,Ring A is an optionally substituted benzene ring or an optionallysubstituted thiazole ring, X¹ is an oxygen atom, X² is a bond or—S(O)_(n)— (wherein n is 0, 1 or 2), Y is an oxygen atom or—C(═O)—N(R³)— (wherein R³ is a hydrogen atom, alkyl or aralkyl, and thecarbon atom is bonded to M¹, and the nitrogen atom to M²), M¹, M² and M³may be the same or different and are each independently a bond oralkylene, and M⁴ is alkylene;

(29) A prodrug of the compound as described in the above-mentioned (1);

(30) A medicine comprising the compound as described in theabove-mentioned (1) or a prodrug thereof;

(31) An agent of regulating nuclear receptor PPAR comprising thecompound as described in the above-mentioned (1) or a prodrug thereof;

(32) A prophylactic or therapeutic agent for nuclear receptorPPAR-related diseases comprising the compound as described in theabove-mentioned (1) or a prodrug thereof;

(33) The prophylactic or therapeutic agent as described in theabove-mentioned (32), wherein the nuclear receptor PPAR-related diseasesare lipid metabolism abnormality or sequelae thereof, arterioscleroticdisease or sequelae thereof, diabetes mellitus, or impaired glucosetolerance;

(34) The medicine as described in the above-mentioned (30), which is anagent of raising high-density lipoprotein cholesterol, an agent oflowering triglyceride, an agent of lowering a low-density lipoproteincholesterol or an agent of suppressing progress of arterioscleroticplaque;

(35) An agent of regulating GPR40 receptor function comprising thecompound as described in the above-mentioned (1) or a prodrug thereof;

(36) The agent as described in the above-mentioned (35) which is anagent of regulating insulin secretion, an agent of lowering bloodglucose or an agent of protecting pancreatic β cell;

(37) The agent as described in the above-mentioned (35), which is aprophylactic or therapeutic agent for diabetes mellitus, glucoseintolerance, ketosis, acidosis, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction,cutaneous diseases, arthropathy, osteopenia, arteriosclerosis,thrombotic diseases, dyspepsia, memory and learning disorders, obesity,hypoglycaemia, hypertension, edema, insulin resistant syndrome, unstablediabetes mellitus, lipoatrophy, insulin allergy, insulinoma,lipotoxicity or cancer;

(38) A method of regulating nuclear receptor PPAR, which comprisesadministering to a mammal an effective amount of the compound asdescribed in the above-mentioned (1) or a prodrug thereof;

(39) A method of preventing or treating nuclear receptor PPAR-relateddisease, which comprises administering to a mammal an effective amountof the compound as described in the above-mentioned (1) or a prodrugthereof;

(40) The method as described in the above-mentioned (39), wherein thenuclear receptor PPAR-related diseases is lipid metabolism abnormalityor sequelae thereof, arteriosclerotic disease or sequelae thereof,diabetes mellitus, or impaired glucose tolerance;

(41) A method of raising high-density lipoprotein cholesterol, loweringtriglyceride, lowering low-density lipoprotein cholesterol orsuppressing progress of arteriosclerotic plaque, which comprisesadministering to a mammal an effective amount of the compound asdescribed in the above-mentioned (1) or a prodrug thereof;

(42) A method of regulating GPR40 receptor function, which comprisesadministering to a mammal an effective amount of the compound asdescribed in the above-mentioned (1) or a prodrug thereof;

(43) A method of regulating insulin secretion, lowering blood glucose orprotecting pancreatic β cell, which comprises administering to a mammalan effective amount of the compound as described in the above-mentioned(1) or a prodrug thereof;

(44) A method of preventing or treating diabetes mellitus, glucoseintolerance, ketosis, acidosis, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction,cutaneous diseases, arthropathy, osteopenia, arteriosclerosis,thrombotic diseases, dyspepsia, memory and learning disorders, obesity,hypoglycaemia, hypertension, edema, insulin resistant syndrome, unstablediabetes mellitus, lipoatrophy, insulin allergy, insulinoma,lipotoxicity or cancer, which comprises administering to a mammal aneffective amount of the compound as described in the above-mentioned (1)or a prodrug thereof;

(45) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing an agent of regulating nuclearreceptor PPAR;

(46) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing a prophylactic or therapeutic agentfor nuclear receptor PPAR-related diseases;

(47) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing a prophylactic or therapeutic agentfor lipid metabolism abnormality or sequelae thereof, arterioscleroticdisease or sequelae thereof, diabetes mellitus, or impaired glucosetolerance;

(48) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing an agent of raising high-densitylipoprotein cholesterol, an agent of lowering triglyceride, an agent oflowering a low-density lipoprotein cholesterol or an agent ofsuppressing progress of arteriosclerotic plaque;

(49) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing an agent of regulating GPR40 receptorfunction;

(50) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing an agent of regulating insulinsecretion, an agent of lowering blood glucose or an agent of protectingpancreatic β cell; and

(51) Use of the compound as described in the above-mentioned (1) or aprodrug thereof for manufacturing a prophylactic or therapeutic agentfor diabetes mellitus, glucose intolerance, ketosis, acidosis, diabeticneuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia,sexual dysfunction, cutaneous diseases, arthropathy, osteopenia,arteriosclerosis, thrombotic diseases, dyspepsia, memory and learningdisorders, obesity, hypoglycaemia, hypertension, edema, insulinresistant syndrome, unstable diabetes mellitus, lipoatrophy, insulinallergy, insulinoma, lipotoxicity or cancer.

In the following, definitions of each symbol will be explained.

R is an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group.

The hydrocarbon group in the “optionally substituted hydrocarbon group”represented by R includes, for example, an aliphatic hydrocarbon group,an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbongroup, an aromatic aliphatic hydrocarbon group, an aromatic hydrocarbongroup and the like. Such a hydrocarbon group has preferably 1 to 15carbon atoms.

The aliphatic hydrocarbon group includes a straight or branchedaliphatic hydrocarbon group having 1 to 15 carbon atoms, for example,alkyl, alkenyl, alkynyl and the like.

Suitable examples of alkyl include an alkyl group having 1 to 10 carbonatoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl,hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and thelike, among those preferably, an alkyl group having 1 to 4 carbon atoms(especially, methyl, ethyl, isopropyl, butyl).

Suitable examples of alkenyl include an alkenyl group having 2 to 10carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl,1-octenyl and the like.

Suitable examples of alkynyl include an alkynyl group having 2 to 10carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl,1-octynyl and the like.

The alicyclic hydrocarbon group includes a saturated or unsaturatedalicyclic hydrocarbon group having 3 to 12 carbon atoms, for example,cycloalkyl, cycloalkenyl, cycloalkadienyl and the like.

Suitable examples of cycloalkyl include a cycloalkyl group having 3 to10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and thelike, among those preferably, cyclohexyl.

Suitable examples of cycloalkenyl include a cycloalkenyl group having 3to 10 carbon atoms, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

Suitable examples of cycloalkadienyl include a cycloalkadienyl grouphaving 4 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

The alicyclic-aliphatic hydrocarbon group includes, for example, thoseformed by binding of the above-mentioned alicyclic hydrocarbon group andaliphatic hydrocarbon group (e.g., cycloalkyl-alkyl, cycloalkenyl-alkyland the like), among those preferably, an alicyclic-aliphatichydrocarbon group having 4 to 9 carbon atoms. Suitable examples of thealicyclic-aliphatic hydrocarbon group include cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl,2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl,cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.

The aromatic aliphatic hydrocarbon group includes, for example, anaromatic aliphatic hydrocarbon group having 7 to 13 carbon atoms (e.g.,an aralkyl group having 7 to 13 carbon atoms, an arylalkenyl grouphaving 8 to 13 carbon atoms and the like) and the like. Suitableexamples of the aromatic aliphatic hydrocarbon group include aphenylalkyl group having 7 to 9 carbon atoms such as benzyl, phenethyl,1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and thelike; a naphthylalkyl group having 11 to 13 carbon atoms such as1-naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, 2-naphthylethyl andthe like; a phenylalkenyl group having 8 to 10 carbon atoms such asstyryl and the like; a naphthylalkenyl group having 12 to 13 carbonatoms such as 2-(2-naphthylvinyl) and the like, and the like.

The aromatic hydrocarbon group (aryl) includes an aromatic hydrocarbongroup having 6 to 14 carbon atoms, for example, phenyl, naphthyl,anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, amongthose preferably, phenyl, 1-naphthyl, 2-naphthyl and the like. Thearomatic hydrocarbon group may be partially hydrogenated, and thepartially hydrogenated aromatic hydrocarbon group includes, for example,tetrahydronaphthalenyl and the like.

The “hydrocarbon group” represented by R is preferably an alkyl grouphaving 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbonatoms, an aralkyl group having 7 to 13 carbon atoms, an aryl grouphaving 6 to 14 carbon atoms and the like.

The heterocycle in the “optionally substituted heterocyclic group”represented by R includes, for example, aromatic heterocycle andnon-aromatic heterocycle.

The aromatic heterocycle includes, for example, a 5- to 7-memberedmonocyclic aromatic heterocycle or fused aromatic heterocycle containing1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and anitrogen atom in addition to carbon atoms as ring-constituting atoms.The fused aromatic heterocycle includes, for example, a ring in whichsuch a 5- to 7-membered monocyclic aromatic heterocycle is fused with a6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or a5-membered ring containing 1 sulfur atom and the like. Suitable examplesof the aromatic heterocycle include furan, thiophene, pyridine,pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole,isoxazole, isothiazole, oxazole, thiazole, oxadiazole, thiadiazole,triazole, tetrazole, quinoline, quinazoline, quinoxaline, benzofuran,benzothiophene, benzoxazole, benzothiazole, benzimidazole, indole,1H-indazole, 1H-pyrrolo[2,3-b]pyrazine, 1H-pyrrolopyridine,1H-imidazopyridine, 1H-imidazopyrazine, triazine, isoquinoline,benzothiadiazole and the like. The aromatic heterocycle is preferably 5or 6-membered aromatic heterocycle, further preferably, furan,thiophene, pyridine, pyrimidine, pyrazole, oxazole, thiazole and thelike.

The non-aromatic heterocycle includes, for example, 5- to 7-memberedmonocyclic non-aromatic heterocycle or fused non-aromatic heterocyclecontaining 1 to 4 heteroatoms selected from an oxygen atom, a sulfuratom and a nitrogen atom in addition to carbon atoms asring-constituting atoms. The non-aromatic fused heterocycle includes,for example, a ring in which such 5- to 7-membered monocyclicnon-aromatic heterocycle is fused with a 6-membered ring containing 1 to2 nitrogen atoms, a benzene ring or a 5-membered ring containing 1sulfur atom and the like. Suitable examples of the non-aromaticheterocycle include pyrrolidine, pyrroline, pyrazolidine, piperidine,piperazine, morpholine, thiomorpholine, hexamethyleneimine, oxazolidine,thiazolidine, imidazolidine, imidazoline, tetrahydrofuran, azepane,tetrahydropyridine and the like.

The hydrocarbon group and heterocyclic group represented by R may have 1to 3 substituents at substitutable position. Such substituent includes,for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine);sulfo; cyano; azido; nitro; nitroso; a C₁₋₆ alkyl group optionallysubstituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like)(e.g., methyl, ethyl, propyl, isopropyl,trifluoromethyl and the like); a C₂₋₆ alkenyl group optionallysubstituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like)(e.g., ethenyl, 1-propenyl, 2-propenyl andthe like); an alkynyl group having 1 to 6 carbon atoms optionallysubstituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like)(e.g., ethynyl, 1-propynyl and the like); aC₃₋₁₀ cycloalkyl group optionally substituted with 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like)(e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like); a C₆₋₁₄aryl group optionally substituted with 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like)(e.g., phenyl, naphthyland the like); an aromatic heterocyclic group optionally substitutedwith 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine andthe like)(e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl and thelike); non-aromatic heterocyclic group optionally substituted with 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike)(e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, piperazinyl and the like); a C₇₋₁₃ aralkyl groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like)(e.g., benzyl, phenethyl,naphthylmethyl and the like); amino optionally mono- or di-substitutedwith a substituent (s) selected from a C₁₋₄ alkyl group optionallysubstituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like)(e.g., methyl, ethyl, propyl, isopropyl andthe like), formyl, a C₂₋₈ acyl group optionally substituted with 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like),and a C₁₋₈ sulfonyl group optionally substituted with 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like); amidino;formyl; a C₂₋₈ acyl group optionally substituted with 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like); a C₁₋₈sulfonyl group optionally substituted with 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like); a C₁₋₈ sulfinyl groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like); phosphono optionally mono- ordi-substituted with a C₁₋₄ alkyl group optionally substituted with 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike)(e.g., methyl, ethyl, propyl, isopropyl and the like); carbamoyloptionally mono- or di-substituted with a C₁₋₄ alkyl group optionallysubstituted with 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine and the like)(e.g., methyl, ethyl, propyl, isopropyl andthe like); sulfamoyl optionally mono- or di-substituted with a C₁₋₄alkyl group optionally substituted with 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like)(e.g., methyl, ethyl,propyl, isopropyl and the like); carboxy; a C₂₋₈ alkoxycarbonyl groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like);hydroxy; a C₁₋₆ alkoxy group optionally substituted with 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like)(e.g.,methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy and the like); aC₂₋₅ alkenyloxy group optionally substituted with 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like)(e.g., allyloxy,crotyloxy, 2-pentenyloxy and the like); a C₇₋₁₃ aralkyloxy groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) (e.g., benzyloxy, phenethyloxyand the like); a C₆₋₁₄ aryloxy group optionally substituted with 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)(e.g., phenyloxy, naphthyloxy and the like); mercapto; a C₁₋₆ alkylthiogroup optionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like)(e.g., methylthio, ethylthio,propylthio, isopropylthio, trifluoromethylthio and the like); a C₇₋₁₃aralkylthio group optionally substituted with 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like) (e.g.,benzylthio, phenethylthio and the like); a C₆₋₁₄ arylthio groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) (e.g., phenylthio, naphthylthioand the like); oxo; thioxo, and the like. Preferred is a halogen atom(especially, fluorine), a C₁₋₆ alkoxy group optionally substituted with1 to 3 halogen atoms and the like.

Suitable examples of the acyl group which the hydrocarbon group or theheterocyclic group represented by R may have as the substituent include,for example, a C₂₋₈ acyl group optionally substituted with 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)(e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, hexanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, crotonyl, benzoyl, nicotinoyl, isonicotinoyl,trifluoroacetyl and the like) and the like.

Suitable examples of the sulfonyl group which the hydrocarbon group orthe heterocyclic group represented by R may have as the substituentinclude, for example, a C₁₋₈ sulfonyl group optionally substituted with1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike) (e.g., methanesulfonyl, ethanesulfonyl, benzenesulfonyl,p-toluenesulfonyl, trifluoromethanesulfonyl and the like) and the like.

Suitable examples of the sulfinyl group which the hydrocarbon group orthe heterocyclic group represented by R may have as the substituentinclude, for example, a C₁₋₈ sulfinyl group optionally substituted with1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike) (e.g., methanesulfinyl, ethanesulfinyl, benzenesulfinyl,p-toluenesulfinyl, trifluoromethanesulfinyl and the like) and the like.

Suitable examples of the phosphono group which the hydrocarbon group orthe heterocyclic group represented by R may have as the substituentinclude, for example, (a C₁₋₄ monoalkyl or dialkyl)phosphono (e.g.,dimethylphosphono; diethylphosphono; diisopropylphosphono;dibutylphosphono; 2-oxido-1,3,2-dioxaphosphinan-2-yl and the like) whichmay form a ring and the like.

Among those, R is preferably an optionally substituted alkyl, anoptionally substituted aryl, an optionally substituted aralkyl, anoptionally substituted cycloalkyl and the like, and the substituent ispreferably 1) a halogen atom; 2) a C₁₋₆ alkyl group optionallysubstituted with 1 to 3 halogen atoms (e.g., methyl, ethyl, propyl,isopropyl, trifluoromethyl and the like); 3) hydroxy; 4) a C₁₋₆ alkoxygroup optionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like)(e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like.

Among those, R is especially preferably a C₁₋₄ alkyl group optionallysubstituted with 1 to 3 halogen atoms or hydroxy, a phenyl groupoptionally substituted with 1 to 3 halogen atoms, a C₃₋₁₀ cycloalkylgroup and the like.

p is 0, 1 or 2. That is, the substituent R is not present, or present atone or two. When R is present at two (p is 2), each R may be the same ordifferent.

R is preferably present at one (p is 1).

R¹ is a hydrogen atom or an optionally substituted hydrocarbon group.

The “hydrocarbon group” in R¹ has the same meaning as the “hydrocarbongroup” in R, among those preferably, an alkyl such as ethyl and the like(especially, an alkyl group having 1 to 4 carbon atoms). The hydrocarbongroup may be substituted with the substituents exemplified as thesubstituent which the “hydrocarbon group” in R may have, and the like.The position of the substituent may be any substitutable position. Thenumber of the substituent may be one or more. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

R¹ is preferably a hydrogen atom.

R² is an optionally substituted aromatic group.

The “aromatic group” in R² includes an aromatic hydrocarbon group and anaromatic heterocyclic group. The “aromatic hydrocarbon group” has thesame meaning as the “aromatic hydrocarbon group” exemplified as one ofthe “hydrocarbon group” in R, and may be substituted with thesubstituents exemplified as the substituent which the “hydrocarbongroup” in R may have, and the like. The position of the substituent maybe any substitutable position. The number of the substituent may be oneor more. When the number of the substituents is two or more, therespective substituents may be the same or different.

The “aromatic heterocyclic group” in R² has the same meaning as the“aromatic heterocyclic group” exemplified as one of the “heterocyclicgroup” in R, and may be substituted with the substituents exemplified asthe substituent which the “heterocyclic group” in R may have, and thelike. The position of the substituent may be any substitutable position.The number of the substituent may be one or more. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

R² is preferably optionally substituted, an aromatic hydrocarbon grouphaving 6 to 14 carbon atoms (preferably phenyl) and a 5- or 6-memberedaromatic heterocyclic group (preferably pyridyl, furyl, thienyl), amongthose preferably, optionally substituted phenyl. Preferred substituentincludes 1) a halogen atom (e.g., fluorine, chlorine, bromine, iodineand the like); 2) a C₁₋₆ alkyl group optionally substituted with 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike)(e.g., methyl, ethyl, propyl, isopropyl, trifluoromethyl and thelike); 3) a C₆₋₁₄ aryl group (e.g., phenyl and the like); 4) a C₁₋₆alkoxy group optionally substituted with 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like) (e.g., methoxy,ethoxy, trifluoromethoxy and the like); 5) a C₁₋₆ alkylthio groupoptionally substituted with 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) (e.g., methylthio and the like)and the like.

R² is more preferably a C₆₋₁₄ aromatic hydrocarbon group (preferablyphenyl) or 5 or 6-membered aromatic heterocyclic group (preferablypyridyl, furyl, thienyl) which may have respectively 1 to 3 substituentsselected from the above-mentioned 1)-5), among those especiallypreferably, phenyl which may have 1 to 3 substituents selected from theabove-mentioned 1), 2) and 4).

X¹ is an oxygen atom or a sulfur atom.

X¹ is preferably an oxygen atom.

X² is a bond, an oxygen atom or —S(O)_(n)— (wherein n is 0, 1 or 2).

X² is preferably a bond, an oxygen atom or a sulfur atom (n is 0).

Y is a bond, an oxygen atom, —S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)—(R³ is a hydrogen atom, an optionally substituted hydrocarbon group oran optionally substituted heterocyclic group, and m is 0, 1 or 2).

Y is preferably —O—, —S—, or —C(═O)—N(R³)— (R³ has the same meaning asdefined above).

The “hydrocarbon group” in R³ has the same meaning as the “hydrocarbongroup” in R, and is preferably aliphatic hydrocarbon group such asmethyl, propyl, heptyl and the like, an aromatic aliphatic hydrocarbongroup such as benzyl group and the like. The hydrocarbon group may besubstituted with the substituents exemplified as the substituent whichthe “hydrocarbon group” in R may have, and the like, and the like. Theposition of the substituent may be any substitutable position. Thenumber of the substituent may be one or more. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

The “heterocyclic group” in R³ has the same meaning as the “heterocyclicgroup” in R, and may be substituted with the substituents exemplified asthe substituent which the “heterocyclic group” in R may have, and thelike. The position of the substituent may be any substitutable position.The number of the substituent may be one or more. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

R³ is preferably a hydrogen atom, an optionally substituted alkyl, anoptionally substituted aralkyl, an optionally substituted cycloalkyl, anoptionally substituted aryl, and the substituent is preferably 1) ahalogen atom; 2) a C₁₋₆ alkyl group optionally substituted with 1 to 3halogen atoms (e.g., methyl, ethyl, propyl, isopropyl, trifluoromethyland the like); 3) hydroxy; 4) a C₁₋₆ alkoxy group optionally substitutedwith 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine andthe like)(e.g., methoxy, ethoxy, trifluoromethoxy and the like) and thelike.

Among those, R³ is more preferably a hydrogen atom, a C₁₋₄ alkyl groupoptionally substituted with 1 to 3 halogen atoms and the like,especially preferably, a hydrogen atom.

Ring A is an optionally substituted monocyclic aromatic ring oroptionally substituted bicyclic aromatic fused ring, preferably anoptionally substituted monocyclic aromatic ring.

The “monocyclic aromatic ring” in Ring A is a ring which may have aheteroatom (for example, an oxygen atom, nitrogen atom, a sulfur atomand the like) as ring-constituting atoms in addition to carbon atoms,and is aromatic. It includes benzene and a monocyclic aromaticheterocycle such as furan, thiophene, pyridine, pyrimidine, pyridazine,pyrazine, pyrrole, imidazole, pyrazole, isoxazole, isothiazole, oxazole,thiazole, oxadiazole, thiadiazole, triazole, tetrazole and the like,among those preferably, benzene, thiazole and oxazole and the like,especially preferably, benzene and thiazole. The monocyclic aromaticring may be substituted with the substituent exemplified as thesubstituent which the “hydrocarbon group” and “heterocyclic group” in Rmay have, and the like, preferably with a C₁₋₆ alkyl group or a C₁₋₆alkoxy group. The aromatic ring in Ring A may be substituted with suchsubstituents of 1 or 2. Of course, the substituent is bonded at thesubstitutable position of the aromatic ring.

The “bicyclic aromatic fused ring” in Ring A is a ring obtained byfusion of two rings and is aromatic, and may contain a heteroatom (forexample, an oxygen atom, nitrogen atom, a sulfur atom and the like) aseach ring-constituting atom in addition to carbon atoms. The fused ringincludes, for example, naphthalene, quinoline, quinazoline, quinoxaline,benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole,indole, 1H-indazole, 1H-pyrrolo[2,3-b]pyrazine, 1H-pyrrolopyridine,1H-imidazopyridine, 1H-imidazopyrazine, triazine, isoquinoline,benzothiadiazole, among those preferably, naphthalene, benzofuran,benzothiophene, benzoxazole, benzothiazole and the like. The fused ringmay be substituted with the substituents exemplified as the substituentwhich the “hydrocarbon group” and “heterocyclic group” in R may have,and the like. The bicyclic aromatic fused ring in Ring A may besubstituted with such substituents of 1 or 2. Of course, the substituentis bonded at the substitutable position of the bicyclic aromatic fusedring.

When Ring A is the optionally further substituted benzene ring, bindingpositions of M² and M³ on the benzene ring is preferably para or meta,among those especially preferably, meta substitution, that is, theformula:

in the formula (I) is the formula:

(wherein Ring A′ is an optionally further substituted benzene ring).

M¹, M² and M³ may be the same or different and are each independently abond or an optionally substituted divalent aliphatic hydrocarbon group,and M⁴ is an optionally substituted divalent aliphatic hydrocarbongroup.

The “divalent aliphatic hydrocarbon group” represented by M¹, M², M³ andM⁴ includes, for example, alkylene, alkenylene, alkynylene and the like.It is preferably a C₁₋₂₀, more preferably a C₁₋₆ divalent aliphatichydrocarbon group, and further preferably,

-   (1) C₁₋₂₀ alkylene (preferably C₁₋₆ alkylene, for example, —CH₂—,    —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH(CH₃)—,    —C(CH₃)₂—, —(CH(CH₃)₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— or    —CH(CH₂CH₂CH₃)—;-   (2) C₂₋₂₀ alkenylene (preferably C₂₋₆ alkenylene, for example,    —CH═CH—, —CH₂—CH═CH—, —C(CH₃)₂—CH═CH—, —CH₂—CH═CH—CH₂—,    —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and the like)-   (3) C₂₋₂₀ alkynylene (preferably C₂₋₆ alkynylene, for example,    —C═C—, —CH₂—C═C—, —CH₂—C═C—CH₂—CH₂— and the like); and the like,    among those especially preferably, C₁₋₆alkylene and C₂₋₆alkenylene    and the like.

The “aliphatic hydrocarbon group” may have a substituent, and thesubstituent includes, for example, the substituents exemplified as thesubstituent which the “hydrocarbon group” in R may have, and the like.The “divalent aliphatic hydrocarbon group” in M¹, M², M³ and M⁴ may besubstituted with such substituents of 1 or 2. Of course, the substituentis bonded at the substitutable position of the “aliphatic hydrocarbongroup”.

M¹ is also preferably an alkylene group having 3 or more (especiallypreferably propylene). Furthermore, M¹, M² and M³ may be the same ordifferent and are each independently preferably a bond, alkylene,alkenylene or alkynylene, and M⁴ is preferably alkylene, alkenylene oralkynylene.

The combination of X² and M³ is preferably such that X² is an oxygenatom or —S(O)_(n)— (wherein n is 0, 1 or 2) and M³ is an optionallysubstituted divalent aliphatic hydrocarbon group.

R, R² and the group represented by the formula:

(wherein the symbols are as defined above) may be substituted at anysubstitutable position of the ring

(wherein the symbols are as defined above), among those preferably atthe substitution position represented by

(wherein the symbols are as defined above).

A compound of the formula (I′) is preferably a compound of the formula(I″):

(wherein the symbols are as defined above), especially in the formula(I″) preferably wherein X¹ is an oxygen atom, X² is an oxygen atom or—S(O)_(n)— (wherein n is 0, 1 or 2), Y is an oxygen atom, M¹ isoptionally substituted C₁₋₃ alkylene (M¹ is preferably an optionallysubstituted methylene), M² is a bond, M³ is a bond or optionallysubstituted methylene (M³ is preferably an optionally substitutedmethylene), and M⁴ is optionally substituted methylene.

Among the compound of the formula (I″), also preferred is a compound ofthe formula (I″) wherein X¹ is an oxygen atom, X² is a bond, Y is anoxygen atom, M¹ is optionally substituted n-propylene, M² and M³ are abond, and M⁴ is optionally substituted methylene.

Among the compound of the formula (I′), also preferred is a compound ofthe formula (I′) wherein Ring A is an optionally substituted monocyclicaromatic heterocycle. Among those, preferred is a compound of theformula (I′) wherein Ring A is an optionally substituted thiazole ringor an optionally substituted oxazole ring, X¹ is an oxygen atom, X is abond, Y is an oxygen atom or —S(O)_(n)— (wherein n is 0, 1 or 2), M¹ isoptionally substituted C₁₋₃ alkylene, M² and M³ are a bond, and M⁴ isoptionally substituted methylene. Among those, especially preferred is acompound of the formula (I′) wherein Ring A is an optionally substitutedthiazole ring, X¹ is an oxygen atom, X² is a bond, Y is —S—, M¹ isoptionally substituted methylene or optionally substituted n-propylene,M² and M³ are a bond, and M⁴ is optionally substituted methylene.

A compound of the formula (I′″):

(wherein the symbols are as defined above) among the compound of formula(I′), is also included in one of the preferable embodiments of thepresent invention.

Preferable embodiments of the compound represented by the formula (I) ofthe present invention (hereinafter, referred to as Compound (I)) includea compound of the formula (I) wherein R is optionally substituted alkyl,aryl or cycloalkyl, p is 0 or 1, R¹ is a hydrogen atom, R² is anoptionally substituted phenyl group, Ring A is an optionally substitutedbenzene ring or an optionally substituted thiazole ring, X¹ is an oxygenatom, X² is a bond, an oxygen atom or —S(O)_(n)— (wherein n is 0, 1 or2), Y is an oxygen atom or —C(═O)—N(R³)— (wherein R³ is a hydrogen atom,alkyl or aralkyl, and the carbon atom is bonded to M¹, and the nitrogenatom to M²), M¹, M² and M³ may be the same or different and are eachindependently a bond or alkylene, and M⁴ is alkylene.

Salts of Compound (I) is preferably pharmacologically acceptable salts,and include, for example, a salt with an inorganic base, a salt with anorganic base, a salt with an inorganic acid, a salt with an organicacid, a salt with a basic or acidic amino acid, etc.

Preferable examples of the salt with an inorganic base include an alkalimetal salt such as sodium salt, potassium salt, lithium salt, etc.; analkaline earth metal salt such as calcium salt, magnesium salt, etc.;aluminum salt; ammonium salt; etc.

Preferable examples of the salt with an organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc.

Preferable examples of the salt with an inorganic acid include a saltwith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc.

Preferable examples of the salt with an organic acid include a salt withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.

Preferable examples of the salt with a basic amino acid include a saltwith arginine, lysine, ornithine, etc.

Preferable examples of the salt with an acidic amino acid include a saltwith aspartic acid, glutamic acid, etc.

The prodrug of Compound (I) or a salt thereof means a compound which isconverted to Compound (I) under the physiological condition or with areaction by an enzyme, an gastric acid, etc. in the living body, thatis, a compound which is converted to Compound (I) by enzymaticoxidation, reduction, hydrolysis, etc.; a compound which is converted toCompound (I) with hydrolysis by gastric acid, etc.; etc. Examples of theprodrug of Compound (I) include a compound wherein an amino group ofCompound (I) is substituted with acyl, alkyl, phosphoric acid, etc.(e.g. a compound wherein an amino group of Compound (I) is substitutedwith eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl,etc.); a compound wherein an hydroxy group of Compound (I) issubstituted with acyl, alkyl, phosphoric acid, boric acid, etc. (e.g. acompound wherein an hydroxy group of Compound (I) is modified withacetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl, tetrahydropyranyl, etc.); a compoundwherein a carboxy group of Compound (I) is modified with ester, amide,etc. (e.g. a compound wherein a carboxy group of Compound (I) ismodified with ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbony-loxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester,cyclohexyloxycarbonylethyl ester, methyl amide, etc.); etc. Thesecompounds can be manufactured by per se known method from Compound (I).

In addition, the prodrug of Compound (I) may be a compound which isconverted into Compound (I) under the physiological conditions asdescribed in “Pharmaceutical Research and Development”, Vol. 7 (DrugDesign), pages 163-198 published in 1990 by Hirokawa Publishing Co.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵Iand the like) and the like.

Compound (I) may be anhydride or hydrate.

Compound (I) or a salt thereof (hereinafter, sometimes simply referredto as the compound of the present invention) has low toxicity and can beused as a medicine for mammals (e.g., human, mouse, rat, rabbit, dog,cat, bovine, horse, pig, monkey etc.), preferably a prophylactic ortherapeutic agent for various diseases to be mentioned below as itselfor as an admixture with a pharmacologically acceptable carrier.

Examples of the pharmacologically acceptable carriers include variousorganic or inorganic carriers which are generally used in this field.For example, an excipient, a lubricant, a binder, a disintegratingagent, etc. are used in solid formulations; and a solvent, asolubilizer, a suspending agent, an isotonizing agent, a buffer, asoothing agent, etc. are used in liquid formulations. In addition, ifdesired, an additive such as a preservative, antioxidant, a colorant, asweetener, etc. may be used.

The suitable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, dextrin, α-nized starch, crystallinecellulose, low-substituted hydroxypropylcellulose,carboxymethylcellulose sodium, arabia gum, dextrin, pullulan, lightsilicic anhydride, synthetic aluminum silicate, magnesiumaluminometasilicate, etc.

Suitable examples of the lubricant include magnesium stearate, calciumstearate, talc, colloidal silica, etc.

The suitable examples of the binder include, for example, α-nizedstarch, cane sugar, gelatin, arabia gum, methylcellulose,carboxymethylcellulose, carboxymethylcellulose sodium, crystallinecellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, etc.

The suitable examples of the disintegrator include, for example,lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulosecalcium, croscarmellose sodium, carboxymethylstarch sodium, lightsilicic anhydride, low-substituted hydroxypropylcellulose, etc.

The suitable examples of the solvent include, for example, water forinjection, physiological saline, Ringer's solution, alcohol, propyleneglycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonoil, etc.

The suitable examples of the solubilizer include, for example,polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,sodium carbonate, sodium citrate, sodium salicylate, sodium acetate,etc.

The suitable examples of the suspending agent include, for example,surfactants such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glyceryl monostearate, etc.; and hydrophilic macromolecularsubstances such as polyvinyl alcohol, polyvinylpyrrolidone,carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, etc.; polysorbates,polyoxyethylene hydrogenated castor oil, etc.

The suitable examples of the isotonizing agent include, for example,sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.

The suitable examples of the buffer include, for example, a buffersolution such as phosphate, acetate, carbonate, citrate, etc.

The suitable examples of the soothing agent include, for example, benzylalcohol, etc.

The suitable examples of the preservative include, for example,p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc.

The suitable examples of the antioxidant include, for example, sulfites,ascorbic acid salts, etc.

The suitable examples of the colorant include, for example,water-soluble food tar colors (e.g., Food Color Red No. 2 and 3, FoodColor Yellow No. 4 and No. 5, and Food Color Blue No. 1 and No. 2; andwater-insoluble lake colors (e.g., aluminate of the above-mentionedwater-soluble food tar colors), natural colors (e.g., β-carotene,chlorophyll, colcothar and the like), etc.

The suitable examples of the sweetener include, for example, saccharinsodium, dipotassium glycyrrhizinate, aspartame, stevia, etc.

Formulation of the medicine of the present invention includes, forexample, oral preparations such as tablets, capsules (includingsoftcapsule and microcapsule), granules, powders, syrups, emulsion,suspension, etc.; and non-oral preparations such as injections (e.g.,subcutaneous injections, intravenous injections, intramuscularinjections, peritoneal injections, etc.), external preparations (e.g.,nasal preparations, transdermal preparations, ointments, etc.),suppositories (e.g., rectal suppositories, vaginal suppositories, etc.),pellet, drops, sustained release preparations (e.g., sustainedmicrocapsule, etc.), eye-drops and the like, which can be safelyadministered orally or non-orally, respectively.

The medicine of the present invention can be produced according to apublicly known method used in the field of a preparation technique, forexample, the method described in the Japanese Pharmacopoeia. Specificmethods of preparing the preparations will be decribed below.

The oral preparation can be produced by adding an excipient (e.g.,lactose, sucrose, starch, D-mannitol, etc.), a disintegrant (e.g.,carboxymethylcellulose calcium, etc.), a binder (e.g., α-nized starch,arabia gum, carboxymethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, etc.), or a lubricant (e.g., talc, magnesiumstearate, polyethylene glycol 6000, etc.), etc. to active ingredients,followed by compressing it and, coating the formulated product with acoating agent for the purpose of taste masking, enteric dissolution orsustained release according to a publicly known method, if necessary.

The coating agent includes, for example, sugar-coating agent,water-soluble film-coating agent, enteric film-coating agent, sustainedrelease film-coating agent and the like.

The sugar-coating agent includes, for example, sucrose, which may beused in combination with one or more of talc, precipitated calciumcarbonate, gelatin, arabia gum, pullulan, Carnauba Wax, etc.

The water-soluble film-coating agent includes, for example, cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and methylhydroxyethylcellulose; syntheticpolymers such as polyvinylacetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trademark), Rohm andHaas Company], polyvinylpyrrolidone; polysaccharides such as pullulanand the like.

The enteric film-coating agent includes, for example, cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetatosuccinate,carboxymethylethylcellulose and cellulose acetate phthalate; acrylatepolymers such as methacrylate copolymer L [Eudragit L (trademark), Rohmand Haas Company], methacrylate copolymer LD [Eudragit L-30D55(trademark), Rohm and Haas Company] and methacrylate copolymer S[Eudragit S (trademark), Rohm and Haas Company]; natural substances suchas Shellac and the like.

The sustained release film-coating agent includes, for example,cellulose polymers such as ethylcellulose; acrylate polymers such asaminoalkylmethacrylate copolymer RS [Eudragit RS (trademark), Rohm andHaas Company], ethyl acrylate and/or methyl methacrylate copolymersuspension [Eudragit NE (trademark), Rohm and Haas Company], etc.

The above-mentioned coating agents may be used in a suitable mixture oftwo or more. Also, a light-blocking agent such as titanium oxide andiron sesquioxide may be used in coating.

The injection preparation can be produced by dissolving, suspending oremulsifying active ingredients in aqueous solvent (e.g., distilledwater, physiological saline, Ringer's solution, etc.) or oily solvent(e.g., vegetable oils such as olive oil, sesame oil, cotton oil and cornoil, propylene glycol, etc.) with a dispersing agent (e.g., polysorbate80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol,carboxymethylcellulose, and sodium alginate, etc.), a preservative(e.g., methyl paraben, propyl parabens, benzyl alcohol, chlorobutanol,phenol, etc.), an isotonizing agent (e.g., sodium chloride, glycerin,D-mannitol, D-sorbitol, glucose, etc), etc. If desired, additives suchas a solubilizer (e.g., sodium salicylate, sodium acetate, etc.), astabilizer (e.g., human serum albumin, etc.), a soothing agent (e.g.,benzyl alcohol, etc.) may be used.

The compound of the present invention has actions of ameliorating bloodlipid metabolism, ameliorating plasma lipid composition, lowering bloodglucose, lowering blood insulin, ameliorating insulin resistance,potentiating insulin sensitivity, controlling retinoid-related receptoror the like.

The controlling action means any of agonist action and antagonistaction.

Furthermore, the retinoid-related receptor is included in a nucleusreceptor, and is a DNA-binding transcription factor whose ligand is asignal molecule such as oil-soluble vitamins etc., which may be any of amonomer receptor, a homodimer receptor and a heterodimer receptor.

Herein, examples of the monomer receptor include retinoid 0 receptor(hereinafter also abbreviated as ROR) α (GenBank Accession No. L14611),RORβ (GenBank Accession No. L14160), RORγ (GenBank Accession No.U16997); Rev-erbα (GenBank Accession No. M24898), Rev-erbβ (GenBankAccession No. L31785); ERRα (GenBank Accession No. X51416), ERRβ(GenBank Accession No. X51417); Ftz-FIα (GenBank Accession No. S65876),Ftz-FIβ (GenBank Accession No. M81385); TIx (GenBank Accession No.S77482); GCNF (GenBank Accession No. U14666) and the like.

Examples of the homodimer receptor include homodimers formed by retinoidX receptor (hereinafter also abbreviated as RXR) a (GenBank AccessionNo. X52733), RXRp (GenBank Accession No. M84820), RXRγ (GenBankAccession No. U38480); COUPα (GenBank Accession No. X12795), COUPβ(GenBank Accession No. M64497), COUPγ (GenBank Accession No. X12794); TR2α (GenBank Accession No. M29960), TR 2β (GenBank Accession No. L27586);HNF 4α (GenBank Accession No. X76930), HNF 4γ (GenBank Accession No.Z49826) and the like.

Examples of the heterodimer receptor include heterodimers formed by theabove-mentioned retinoid X receptor (RXRα, RXRβ or RXRγ) and onereceptor selected from retinoid A receptor (hereinafter also abbreviatedas RAR) α (GenBank Accession No. X06614), RARβ (GenBank Accession No.Y00291), RARγ (GenBank Accession No. M24857); thyroid hormone receptor(hereinafter also abbreviated as TR) α (GenBank Accession No. M24748),TRβ (GenBank Accession No. M26747); vitamin D receptor (VDR) (GenBankAccession No. J03258); peroxisome proliferator-activated receptor(hereinafter also abbreviated as PPAR) a (GenBank Accession No. L02932),PPARβ (PPARδ) (GenBank Accession No. U10375), PPARγ (GenBank AccessionNo. L40904); LXRα (GenBank Accession No. U22662), LXRβ (GenBankAccession No. U14534); FXR (GenBank Accession No. U18374); MB67 (GenBankAccession No. L29263); ONR (GenBank Accession No. X75163); and NURa(GenBank Accession No. L13740), NURβ (GenBank Accession No. X75918) andNURγ (GenBank Accession No. U12767).

The compound of the present invention has an excellent ligand activityfor peroxisome proliferator-activated receptors (PPARα, PPARβ (PPARδ),PPARγ) among the above-mentioned retinoid-involved receptors, and isuseful as an agonist, a partial agonist, an antagonist or a partialantagonist.

Further, the compound of the present invention has an excellent ligandactivity for the peroxisome proliferator-activated receptors inheterodimer receptors formed from a retinoid X receptor and theperoxisome proliferator-activated receptor (e.g., heterodimer receptorsformed from RXRα and PPARδ, heterodimer receptors formed from RXRα andPPARγ, etc.).

Accordingly, the compound of the present invention can be usedadvantageously as a peroxisome proliferator-activated receptor ligand.

Therefore, the compound of the present invention is useful as aprophylactic or therapeutic agent for PPAR-related diseases (forexample, lipid metabolism abnormality and sequelae thereof,arteriosclerotic disease and sequelae thereof, diabetes mellitus,impaired glucose tolerance and the like).

Since the compound of the present invention has an action of increasinghigh-density lipoprotein (HDL) cholesterol while lowering low-densitylipoprotein (LDL) cholesterol, it has an action of increasing plasmaanti-arteriosclerotic index [(HDL cholesterol/total cholesterol)×100]with an action of lowering plasma triglyceride. Therefore, the compoundof the present invention is useful as an agent of increasinghigh-density lipoprotein (HDL) cholesterol, an agent of loweringlow-density lipoprotein (LDL) cholesterol and an agent of loweringtriglyceride. The agent of the present invention is useful as aprophylactic or therapeutic agent for diseases based on suchpharmacological actions. That is, it is particularly useful as aprophylactic or therapeutic agent in a mammal (e.g., mouse, rat,hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, human and thelike) for hyperlipidemia, especially hyper-LDL cholesterolemia,hyperlipoproteinemia and hypertriglyceridemia, hypo-HDL cholesterolemia,and arteriosclerotic disease and sequelae thereof generated from them,acute coronary syndrome such as atherosclerosis, peripheral arterialocclusion, acute myocardial infarction, unstable angina pectoris and thelike, re-stenosis following percutaneous transluminal coronaryangioplasty (PTCA), ischemic cardiac diseases such as myocardialinfarction, angina pectoris and the like, arteriosclerosis involvingvascular calcification and the like, intermittent claudication, cerebralstroke (cerebral infarction, cerebral embolism, cerebral hemorrhage andthe like), lacunar infarction, cerebrovascular dementia, gangrene,glomerulosclerosis, renopathy, Tangier disease and the like.

The compound of the present invention is useful as a prophylactic ortherapeutic agent for primary hypo-HDL-emia and the like which is notcurable only by LDL cholesterol lowering action, as compared with anagent having only LDL cholesterol lowering action but not having HDLcholesterol increasing action. The eventual object of a therapeuticagent for hyperlipidemia is to prevent onset of lethal diseases such ascardiac infarction and the like, and thus an HDL cholesterol increasingagent can prevent more strongly onset of cardiac infarction and the likealthough an agent having only LDL cholesterol lowering action but nothaving HDL cholesterol increasing action is also recognized to haveprophylactic effects somewhat for onset of cardiac infarction and thelike. Furthermore, the compound of the present invention is alsoeffective for patients or diseases or symptoms for which an agent havingonly LDL cholesterol lowering action but not having HDL cholesterolincreasing action is not recognized to show therapeutic effects (forexample, refractory hyperlipidemia and the like), and can suppress onsetrate of lethal diseases such as cardiac infarction and the like even inhuman having normal serum lipid level, and ameliorate the therapeuticeffects.

Furthermore, the compound of the present invention is suitable for thetreatment of diseases associated with excessive cell growth. A mainexample of the diseases associated with excessive cell growth is tumor.It has been reported that tumor growth can be suppressed by loweringtotal serum cholesterol or LDL cholesterol or VLDL cholesterol (Lancet,339, p 1154 (1992)). Therefore, the compound of the present inventioncan treat tumor because they have an LDL cholesterol or VLDL cholesterollowering action. It can be used for the treatment of tumor alone or incombination with known therapeutic methods. Other applicable diseasesinclude hyperproliferative skin diseases such as psoriasis, basal cellcancer, squamous cell carcinoma, keratosis and keratosis diseases.

The hyperproliferative vascular diseases such as angiostenosis andocclusion caused by surgical means such as PTCA (percutaneoustransluminal coronary angioplasty) or bypass surgery are based on thegrowth of smooth muscle cells, and the compound of the present inventionis also suitable for the treatment or prophylaxis of these diseases inview of its LDL cholesterol and VLDL cholesterol lowering action. Forthis end, the compound is used alone or in combination with known activecompound such as heparin and the like that can be administeredintravenously, preferably given by oral administration.

The compound of the present invention has a blood HDL cholesterolincreasing action. By the increase in the blood HDL cholesterol, exportof cholesterol from the cell with excess cholesterol is promoted(Current Opinion in Lipidology 4: 392-400). Thus, the compound of thepresent invention is suitable for the prophylaxis or treatment ofatherosclerosis. In consideration of biological characteristics thereof,the Compounds are particularly suitable for the prophylaxis or treatmentof arteriosclerotic vascular lesion and sequelae thereof, such ascoronary disease (CHD), cerebral ischemia, intermittent claudication,gangrene and the like.

Another use of the compound of the present invention is based onanti-oxidant action of HDL. The blood lipid peroxide concentration isfar higher in HDL than in LDL, and HDL has a role of preventingperoxidation of lipid that occurs in living organisms, such as oxidationof LDL and the like (Current Opinion in Lipidology 4: 392-400, CurrentOpinion in Lipidology 5: 354-364).

Yet another use of the compound of the present invention includeshypertension and sequelae thereof. Hyperlipidemia aggravatesarteriosclerosis and induces hypertension. In contrast, HDL is known toprevent biosynthesis and to inhibit release of EDRF (epithelium-derivedrelaxing factor) by oxidized LDL, and increase prostacyclin, which is avascular relaxing factor, in macrophages (Current Opinion in Lipidology5: 354-364). In view of the lipid-lowering action and blood HDLcholesterol increasing action of the compound of the present invention,it is suitable for the prophylaxis or treatment of hypertension andsequelae thereof, such as coronary heart disease (CHD), cerebralischemia and the like. For this end, the compound of the presentinvention or a salt thereof is used alone or in combination with apharmaceutical agent exemplified below and can be administered. Thepossible combinations includes, for example, angiotensin-II antagonists[e.g., losartan potassium (NU-LOTAN), candesartan cilexetil (BLOPRESS)and the like], ACE inhibitors [e.g., enalapril maleate (RENIVASE),lisinopril (ZESTRIL, LONGES), delapril hydrochloride (ADECUT), captopriland the like], calcium antagonists [e.g., amlodipine tosilate (AMLODIN,NORVASC), manidipine hydrochloride (CALSLOT) and the like], hypotensivediuretic, a receptor blocker, β receptor blocker and the like.

Some of the possible use of the compound of the present invention isbased on the cell protective action from cytotoxic secretions such asgastric juice, pancreatic juice, bile and the like. Body fluid-tissueinterfacial cells mainly expresses apo J, and form a natural barrieragainst cytotoxic secretions such as gastric juice, pancreatic juice,bile and the like, and HDL is a carrier of apo J (clusterin) (CurrentOpinion in Lipidology 4: 392-400). In consideration of the blood HDLcholesterol increasing action of the compound of the present invention,the compound of the present invention is suitable for the prophylaxis ortreatment of gastric ulcer, pancreatitis, hepatitis and the like.

Some of still other possible use of the compound of the presentinvention is based on cell growth activity. HDL promotes cell growth ofvascular endothelial cells (EC), corneal endothelium and the like, aloneor together with growth factor, and HDL promotes growth of humanlymphocytes (Current Opinion in Lipidology 3: 222-226). The compound ofthe present invention has a blood HDL cholesterol increasing action. Inconsideration of these cell growth activities, it is suitable for theprophylaxis or treatment of arteriosclerotic vascular lesion andsequelae thereof, such as coronary disease, corneal injury and the like.In addition, it is also suitable for the prophylaxis or treatment ofdiseases based on lowered immunity, such as infectious diseases,malignant tumor and the like. Furthermore, HDL specifically acts onhuman placental transplanted tissue to cause secretion of lactogen, aswell as promotes secretion of apoE from macrophages (Current Opinion inLipidology 3: 222-226). In consideration of the secretion promotingactivity, the compound of the present invention is also suitable for theprophylaxis or treatment of fetal hypoplasia and the like.

A more noteworthy application example of the compound of the presentinvention includes secondary hyperlipidemia. This includes diabetesmellitus, insulin resistance (syndrome X), hypothyroidism, nephroticsyndrome, chronic renal failure and the like, and these diseases causeonset of hyperlipidemia. In most cases, it is said that hyperlipidemiaaggravates these diseases, thereby forming what is called a viciouscircle. In view of the lipid lowering action, the compound of thepresent invention is also suitable for the treatment of these diseasesand prevention of progression thereof. For this end, the compounds ofthe present invention are used alone or in combination with a knownactive compound, i.e., for combined use with therapeutic drugs ofdiabetes mellitus, for example, (1) diuretic (e.g., furosemide,spironolactone, etc.), (2) sympathetic suppressant (e.g., atenolol,etc.), (3) angiotensin II antagonists (e.g., losartan, candesartan,etc.), (4) angiotensin I-converting enzyme inhibitors (e.g., enalaprilmaleate, delapril hydrochloride, etc.), (5) calcium antagonists (e.g.,nifedipine, manidipine hydrochloride, etc.) and the like, for combineduse with a therapeutic drug of hypothyroidism, dry thyroid,levothyroxine sodium, liothyronine sodium and the like, for combined usewith a therapeutic drug of renal disease, prednisolone, sodiummethylprednisolone succinate, furosemide, bumetanide, azosemide and thelike, preferably by oral administration.

The compound of the present invention is also useful for the prophylaxisor treatment of Alzheimer's disease. Increase of blood cholesterol isknown as a risk factor of Alzheimer's disease. The compound of thepresent invention can be used for the prophylaxis or treatment ofAlzheimer's disease, based on its superior HDL cholesterol increasingand lipid lowering action thereof. For this end, the compound of thepresent invention can be administered alone or in combination withpharmaceutical agents exemplified in the following. The possiblecombination in this case includes, for example, acetylcholine esteraseinhibitors (e.g., ARICEPT, EXELON and the like), amyloid β productionand/or secretion inhibitors (e.g., γ or β selectase inhibitors such asJT-52, LY-374973 and the like, SIB-1848 and the like), amyloid Pcoagulation inhibitors (e.g., PTI-00703, BETABLOC (AN-1792) and thelike) and the like.

A still noteworthy indication for the use of the compound of the presentinvention is osteoporosis associated with increase of blood cholesterol.By the superior lipid-lowering action, the compound of the presentinvention can be used for the prophylaxis or treatment of osteoporosisassociated with increase of blood cholesterol. For this end, thecompound of the present invention can be administered alone or incombination with pharmaceutical agents exemplified in the following. Thepossible combination in this case includes, for example, sex hormone andrelated pharmaceutical agents [e.g., estrogen preparations, ipriflavone(osten), raloxifene, osateron, tibolone and the like], calcitonins,vitamin D preparations [e.g., alfacalcidol, calcitriol and the like],bone resorption inhibitors such as bisphosphonic acids (e.g.,etidronate, clodronate, etc.) and the like, osteogenesis promoters suchas fluorine compounds, PTH and the like, and the like.

In addition, the compound of the present invention is suitable for thetreatment of the diseases related to hyperchylomicronemia such as acutepancreatitis. As the onset mechanism of pancreatitis, it is said thatchylomicron produces fine thrombus in pancreatic capillary, ortriglyceride is decomposed by pancreatic lipase due tohyperchylomicronemia and the resulting free fatty acid increases tocause strong focal irritation. Since the compound of the presentinvention has a triglyceride-lowering action, it can treat pancreatitis,wherein it can be used alone or in combination with known treatmentmethod for the treatment of pancreatitis. For the treatment of thisdisease, the compound of the present invention can be administeredorally or topically, wherein it can be used alone or in combination withknown active compounds. The components that can be combined in this caseinclude, for example, aprotinin (trasylol), gabexate mesylate (FOY),nafamostat mesylate (futhan), citicoline (nicholin), urinastatin(miraclid) and the like for enzyme inhibition therapy. In addition, forremoval of pain, anticholinergic drugs, normarcotic analgesics ornarcotic is also used.

A yet still possible use of the compound of the present invention isinhibition of thrombus formation. Blood triglyceride level and factorVII involved in blood coagulation are in positive correlation, whereinan intake of α-3 fatty acid lowers triglyceride level as well asinhibits coagulation. Therefore, hypertriglyceridemia promotes formationof thrombus. In addition, since VLDL of hyperlipidemia patientsincreased secretion of plasminogen activator inhibitor from vascularendothelial cells more strongly than did regular lipidemia patients,triglyceride is also considered to degrade fibrinolytic activity.Therefore, in view of the triglyceride-lowering action, the compound ofthe present invention is suitable for the prophylaxis or treatment ofthrombus formation. For this end, it can be used alone or in combinationwith known therapeutic drugs mentioned below, preferably by oraladministration.

Prophylactic or therapeutic drug of thrombus formation: bloodcoagulation inhibitors [e.g., heparin sodium, heparin calcium, warfarincalcium (warfarin), Xa inhibitor], thrombolytic agents [e.g., tPA,urokinase], anti-platelet drugs [e.g., aspirin, sulfinpyrazone(Anturan), dipyridamole (Persantin), ticlopidine (Panaldine), cilostazol(Pletal), GPIIb/IIIa antagonists (reopro)] coronary vasodilators:nifedipine, diltiazem, nicoradil, nitrous acid agents; cardiac muscleprotective drug: heart ATP-K opener, endothelin antagonists, urotensinantagonists and the like.

A yet still possible use of the compound of the present invention isbased on increase of ABCA1m or LXR (liver X receptor) a expression. Theperoxisome proliferators-activated receptor agonist is known to increaseexpression of ABCA1m or LXRA (Nat. Med., vol. 7, p53 (2001), Proc. Natl.Acad. Sci. U.S.A., vol. 98, p5306 (2001), Mol. Cell, vol. 7, p161(2001), Mol. Endocrinol., vol. 14, p741 (2000)). ABCA1 binds toapoprotein (e.g., apoAI, apoAII and the like) or apolipoprotein (e.g.,high-density lipoprotein, HDL) present in the living body, whereby itcan export intracellular cholesterol to the outside of the cells.Furthermore, the cholesterol exported to the outside of the cells istransported to a tissue having low cholesterol content. That is, thecompound of the present invention is useful for regulating cholesteroldistribution in the body.

Therefore, based on the action of exporting intracellular cholesterol,the compound of the present invention is useful as a prophylactic and/ortherapeutic agent for diseases such as hypo-HDL-emia; Tangier disease;coronary disease (e.g., myocardial infarction, angina pectoris, silentmyocardial ischemia and the like); carotid arteriosclerosis;cerebrovascular disorders (e.g., cerebral stroke, cerebral infarctionand the like); occlusive arteriosclerosis; fatty liver; cirrhosis;diabetic complications; cutaneous diseases; xanthoma; joint diseases;proliferative diseases; peripheral arterial occlusion; ischemicperipheral circulation disorders; obesity; cerebrotendinousxanthomatosis (CTX); glomerulonephritis; vascular hypertrophy; vascularhypertrophy following intervention (percutaneous transluminal coronaryangioplasty, percutaneous transluminal coronary revascularization, stentimplantation, coronary endoscopy, intravascular ultrasound,intracoronary thrombolytic therapy and the like); re-occlusion and/orre-stenosis following bypass surgery; hyperlipidemia-related potentrenopathy and/or nephritis or pancreatitis; hyperlipidemia (e.g.,postprandial hyperlipidemia); intermittent claudication; deep veinthrombosis; malarial encephalopathy and the like, or an agent ofsuppressing progress thereof (comprising suppressing progress ofarteriosclerotic plaque in type II diabetes mellitus and the like).

Furthermore, based on the action of transporting cholesterol to a tissuehaving low cholesterol content, the compound of the present invention isuseful as a prophylactic and/or therapeutic agent, for example, fordiseases involved with Alzheimer's disease, wound, hypoplasia and thelike; and an agent of promoting cure after surgery, including accidentor organ transplant.

Furthermore, based on the action of increasing LXRa expression, thecompound of the present invention can increase intracellular LXRAcontent. Since the LXRA can express ABCA1 mRNA, the compound of thepresent invention is useful as a prophylactic and/or therapeutic agentfor the above-mentioned various diseases exemplified as the diseasesinvolving ABCA1 expression increase.

The compound of the present invention can be used as, for example, aprophylactic or therapeutic agent of diabetes mellitus (e.g., type Idiabetes mellitus, type II diabetes mellitus, gestational diabetesmellitus, etc.); a prophylactic or therapeutic agent of hyperlipidemia(e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-emia,postprandial hyperlipemia, etc.); an agent for ameliorating insulinresistance; an insulin sensitizer; a prophylactic or therapeutic agentof impaired glucose tolerance (IGT); and an agent for preventingprogress from impaired glucose tolerance to diabetes mellitus.

Regarding diagnostic criteria of diabetes mellitus, new diagnosticcriteria were reported by the Japan Diabetes Society in 1999.

According to this report, diabetes mellitus is a condition wherein thefasting blood glucose level (glucose concentration in venous plasma) isnot less than 126 mg/dl, the 2-hour value (glucose concentration invenous plasma) of the 75 g oral glucose tolerance test (75 g OGTT) isnot less than 200 mg/dl, or the non-fasting blood glucose level (glucoseconcentration in venous plasma) is not less than 200 mg/dl. In addition,a condition that does not fall within the scope of the above definitionof diabetes mellitus, and which is not a “condition wherein the fastingblood glucose level (glucose concentration in venous plasma) is lessthan 110 mg/dl or the 2-hour value (glucose concentration in venousplasma) of the 75 g oral glucose tolerance test (75 g OGTT) is less than140 mg/dl” (normal type), is called the “borderline type”.

As regards the diagnostic criteria for diabetes mellitus, moreover, newdiagnostic criteria were reported by ADA (American Diabetic Association)in 1997 and by WHO in 1998.

According to these reports, diabetes mellitus is a condition where thefasting blood glucose level (glucose concentration in venous plasma) isnot less than 126 mg/dl, and the 2-hour value (glucose concentration invenous plasma) of the 75 g oral glucose tolerance test is not less than200 mg/dl.

In addition, according to the above reports, impaired glucose toleranceis a condition where the fasting blood glucose level (glucoseconcentration in venous plasma) is less than 126 mg/dl, and the 2-hourvalue (glucose concentration in venous plasma) of the 75 g oral glucosetolerance test is not less than 140 mg/dl and less than 200 mg/dl.Furthermore, according to the ADA report, a condition where the fastingblood glucose level (glucose concentration in venous plasma) is not lessthan 110 mg/dl and less than 126 mg/dl, is called IFG (Impaired FastingGlucose). On the other hand, according to the WHO report, a condition ofIFG (Impaired Fasting Glucose) as such, where the 2-hour value (glucoseconcentration in venous plasma) of the 75 g oral glucose tolerance testis less than 140 mg/dl, is called IFG (Impaired Fasting Glycemia).

The compound of the present invention can also be used as a prophylacticor therapeutic agent of diabetes mellitus, borderline type, impairedglucose tolerance, IFG (Impaired Fasting Glucose) and IFG (ImpairedFasting Glycemia) as defined by the foregoing new diagnostic criteria.Furthermore, the compound of the present invention can be also used toprevent the progression of the borderline type, impaired glucosetolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired FastingGlycemia) to diabetes mellitus.

The compound of the present invention has both action of blood glucoselowering action and plasma lipid composition ameliorating action, andtherefore, it is very useful as a prophylactic and/or therapeutic agentfor arteriosclerotic symptoms in a diabetes mellitus patient.

The compound of the present invention can be also used as a prophylacticor therapeutic agent of diabetic complications (e.g., neuropathy,nephropathy, retinopathy, cataract, macroangiopathy, osteopenia,diabetic hyperosmolar coma, infectious diseases (e.g., respiratoryinfection, urinary tract infection, gastrointestinal tract infection,dermal soft tissue infection, lower limb infection, etc.), diabeticgangrene, xerostomia, decreased sense of hearing, cerebrovasculardisease, peripheral circulatory disturbance, etc.), obesity,osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculouscachexia, diabetic cachexia, hemopathic cachexia, endocrinopathiccachexia, infectious cachexia, cachexia induced by acquiredimmunodeficiency syndrome), fatty liver, hypertension, polycystic ovarysyndrome, renal diseases (e.g., diabetic nephropathy, glomerularnephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, terminal renal disorder, etc.), muscular dystrophy,myocardiac infarction, angina pectoris, cerebrovascular disease (e.g.,cerebral infarction, cerebral stroke), insulin resistant syndrome,syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disorder,tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer,etc.), irritable bowel syndrome, acute or chronic diarrhea, inflammatorydiseases (e.g., Alzheimer's disease, chronic rheumatoid arthritis,spondylitis deformans, osteoarthritis, lumbago, gout, postoperative ortraumatic inflammation, remission of swelling, neuralgia,pharyngolaryngitis, cystitis, hepatitis (including non-alcoholicsteatohepatitis), pneumonia, pancreatitis, inflammatory colitis,ulcerative colitis), visceral obesity syndrome and the like.

Also, the compound of the present invention can be used for amelioratingbellyache, nausea, vomiting, or dysphoria in epigastrium, each of whichis accompanied by gastrointestinal ulcer, acute or chronic gastritis,biliary dyskinesia, cholecystitis and the like.

Furthermore, the compound of the present invention can control (enhanceor inhibit) appetite, and therefore, can be used as a therapeutic agentof leanness and cibophobia (the weight increase in administrationsubjects suffering from leanness or cibophobia) or a therapeutic agentof obesity.

The compound of the present invention has TNF-α suppressing effects(TNF-α production amount lowering effects in a living tissue and TNF-αactivity lowering effects) can be also used as a prophylactic ortherapeutic agent of TNF-α mediated inflammatory diseases. Examples ofsuch inflammatory diseases include diabetic complications (e.g.,retinopathy, nephropathy, neuropathy, macroangiopathy, etc.), chronicrheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago,gout, postoperative or traumatic inflammation, remission of swelling,neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, gastricmucosal injury (including aspirin-induced gastric mucosal injury) andthe like.

The compound of the present invention has an apoptosis inhibitoryactivity, and can be used as a prophylactic or therapeutic agent ofdiseases mediated by promotion of apoptosis. Examples of the diseasesmediated by promotion of apoptosis include viral diseases (e.g., AIDS,fulminant hepatitis, etc.), neurodegenerative diseases (e.g.,Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis,retinitis pigmentosa, cerebellar degeneration, etc.), myelodysplasia(e.g., aplastic anemia, etc.), ischemic diseases (e.g., myocardialinfarction, cerebral stroke, etc.), hepatic diseases (e.g., alcoholichepatitis, hepatitis B, hepatitis C, etc.), joint-diseases (e.g.,osteoarthritis, etc.), atherosclerosis and the like.

The compound of the present invention can be used for reducing visceralfats, inhibiting accumulation of visceral fats, amelioratingglycometabolism, ameliorating lipid metabolism, ameliorating insulinresistance, inhibiting production of oxidized LDL, amelioratinglipoprotein metabolism, ameliorating coronary artery metabolism,preventing or treating cardiovascular complications, preventing ortreating heart failure complications, lowering blood remnant, preventingor treating anovulation, preventing or treating hirsutism, preventing ortreating hyperandrogenism and the like.

The compound of the present invention can be used for prognosisamelioration, for secondary prevention and for inhibition of progress ofthe various diseases described above (e.g., cardiovascular events suchas myocardial infarction, etc.).

Since the compound of the present invention has an action of changingbinding property between fatty acid which is a ligand of GPR40 receptor,and GPR40 receptor, especially GPR40 receptor agonist action, and haslow toxicity, and has few side-effects, it is safe and useful as anagent of regulating GPR40 receptor function, preferably GPR40 agonist.

The compound of the present invention has excellent regulating actionfor GPR40 receptor function in a mammal (for example, mouse, rat,hamster, rabbit, cat, dog, bovine, sheep, monkey, human and the like),and therefore, is useful as an agent of regulating GPR40receptor-associated physiological functions or a prophylactic and/ortherapeutic agent for GPR40 receptor-associated conditions or diseases.

Specifically, a medicine comprising the compound of the presentinvention is useful as an agent of regulating insulin secretion(preferably insulin secretion promoter) or an agent of protectingpancreatic β cell. Furthermore, a medicine comprising the compound ofthe present invention is useful as a prophylactic and/or therapeuticagent for diseases such as diabetes mellitus, glucose intolerance,ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, hyperlipidemia, sexual dysfunction, cutaneous diseases,arthropathy, osteopenia, arteriosclerosis, thrombotic diseases,dyspepsia, memory and learning disorders, obesity, hypoglycaemia,hypertension, edema, insulin resistance, unstable diabetes mellitus,lipoatrophy, insulin allergy, insulinoma, lipotoxicity, cancer and thelike such as disease, especially, diabetes mellitus, glucoseintolerance, ketosis, acidosis, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction,cutaneous diseases, arthropathy, osteopenia, arteriosclerosis,thrombotic diseases, dyspepsia, memory and learning disorders and thelike. Diabetes mellitus includes insulin dependent (Type I) diabetesmellitus and insulin non-dependent (Type II) diabetes mellitus.

The content of Compound (I) of the present invention or apharmacologically acceptable salt thereof in the medicine of the presentinvention is about 0.1% by weight to 90% by weight, usually 0.5% byweight to 50% by weight based on the total weight of the medicine. Thedose may vary depending on administration subject, administration route,the disease and the like, but for example, when orally administered toan adult (60 kg) as a therapeutic agent for arteriosclerosis, an agentof lowering blood glucose or a therapeutic agent for diabeticcomplications, the dose as active ingredient is about 0.1 to 1000mg/day, preferably about 0.5 to 200 mg/day. Compound (I) of the presentinvention or a pharmacologically acceptable salt thereof may beadministered once or twice or three times daily.

The compound of the present invention can be used in combination with adrug such as a therapeutic agent for diabetes mellitus, a therapeuticagent for diabetic complications, an antihyperlipidemic agent, ahypotensive agent, an antiobesity agent, a diuretic agent, achemotherapeutic agent, an immunotherapeutic agent, anti-thrombic agent,an agent of ameliorating cachexia, etc. (hereinafter, abbreviated as acombination drug). The combination drug may be a compound having a lowmolecular weight, or may be a protein, a polypeptide or an antibody,each of which has a high molecular weight, or may be a vaccine and thelike. The administration mode of the compound of the present inventionand the combination drug is not particularly limited, and it issufficient that the compound of the present invention and thecombination drug are combined in administration. Examples of suchadministration mode include: (1) administration of single preparation,which is produced by formulating the compound of the present inventionand the combination drug simultaneously, (2) simultaneous administrationof two kinds of preparations by the same administration route, which areproduced by formulating the compound of the present invention and thecombination drug separately, (3) staggered administration of two kindsof preparations by the same administration route, which are produced byformulating the compound of the present invention and the combinationdrug separately, (4) simultaneous administration of two kinds ofpreparations by different administration route, which are produced byformulating the compound of the present invention and the combinationdrug separately, and (5) staggered administration of two kinds ofpreparations by different administration route (for example, thecompound of the present invention and the combination drug areadministered in this order, or in the reverse order), which are producedby formulating the compound of the present invention and the combinationdrug separately. The dose of the combination drug can be appropriatelyselected based on a clinically employed dose. The compound ratio of thecompound of the present invention and the combination drug can beappropriately determined according to the administration subject, theadministration route, the target disease, the clinical condition, thecombination, and other factors. In cases where the administrationsubject is a human, for instance, the combination drug may be used in anamount of 0.01 to 100 parts by weight per part by weight of the compoundof the present invention.

Examples of the therapeutic agent for diabetes mellitus include insulinpreparations (e.g., animal insulin preparations extracted from thebovine or swine pancreas; human insulin preparations synthesized by agenetic engineering technique using Escherichia coli or a yeast);insulin zinc; protamine insulin zinc; fragment of insulin or derivativesthereof (e.g., INS-1, etc.), agents for ameliorating insulin resistance(e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or itsmaleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614,the compound described in WO99/58510, etc.), α-glucosidase inhibitors(e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanides(e.g., phenformin, metformin, buformin, etc.), insulin secretagogues[sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride,glipizide, glybuzole, etc.), repaglinide, nateglinide, mitiglinide orits calcium salt hydrate, GLP-1, etc.], dipeptidylpeptidase IVinhibitors (e.g., NVP-DPP-278, PT-100, etc.), β3 agonists (e.g.,CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085,AZ-40140, etc.), amylin agonists (e.g., pramlintide, etc.),phosphotyrosine phosphatase inhibitors (e.g., vanadic acid, etc.),gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors,glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLUT(sodium-glucose cotransporter) inhibitors (e.g., T-1095, etc.) and thelike.

Examples of the therapeutic agent for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat (SNK-860), CT-112, etc.),neurotrophic factors (e.g., NGF, NT-3, BDNF, etc.), neurotrophic factorproduction and/or secretion promoters (neurotrophic factor productionand/or secretion promoters described in WO01/14372), PKC inhibitors(e.g., LY-333531, etc.), AGE inhibitors (e.g., ALT946, pimagedine,pyratoxathine, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.),active oxygen scavengers (e.g. thioctic acid, etc.), and cerebralvasodilators (e.g., tiapuride, mexiletine, etc.).

Examples of the antihyperlipidemic agent include an agent of inhibitingbiosynthesis of cholesterol such as HMG-CoA reductase inhibitors such aspravastatin, simvastatin lovastatin, atorvastatin, fluvastatin,lipantil, cerivastatin, itavastatin, ZD-4522 or salts thereof (e.g.,sodium salt and the like) and the like), squalene synthase inhibitors(e.g., the compound as described in WO97/10224)), oxide squalene cyclaseinhibitors (e.g., WO96/11201), squalene epoxidase inhibitors (e.g.,NB-598 and the like) and the like, fibrate compounds (e.g., bezafibrate,beclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, phenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate and the like), ACATinhibitor (e.g., Avasimibe, Eflucimibe and the like), anion-exchangeresin (e.g., cholestyramine and the like), cholesterol absorptioninhibitors (e.g., Ezetimibe, vegetable sterol (e.g., soysterol,γ-oryzanol and the like) and the like), probucol, nicotinic acids (e.g.,nicomol, niceritrol and the like), ethyl eicosapentaenoic acid, and thelike.

Examples of the hypotensive agent include angiotensin converting enzymeinhibitors (e.g., captopril, enalapril, delapril), angiotensin IIantagonists (e.g., candesartan cilexetil, losartan, eprosartan,valsartan, termisartan, irbesartan, tasosartan, etc.), calciumantagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine,efonidipine, etc.), potassium channel opener (e.g., levcromakalim,L-27152, AL 0671, NIP-121 and the like), and clonidine.

Examples of the antiobesity agent include antiobesity drugs acting onthe central nervous system (e.g. dexfenfluramine, fenfluramine,phentermine, sibutramine, anfepramon, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibitors(e.g. orlistat, etc.), β3 agonists (e.g. CL-316243, SR-58611-A,UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), anorecticpeptides (e.g. leptin, CNTF (Ciliary Neurotrophic Factor), etc.) andcholecystokinin agonists (e.g. lintitript, FPL-15849, etc.).

Examples of the diuretic agent include xanthine derivatives (e.g.,theobromine and sodium salicylate, theobromine and calcium salicylate,etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichlormethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide,etc.), anti-aldosterone preparations (e.g., spironolactone, triamterene,etc.), carbonate dehydratase inhibitors (e.g., acetazolamide, etc.),chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside,indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide,bumetanide, furosemide and the like.

Examples of the chemotherapeutic agent include alkylating agents (e.g.,cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil and a derivative thereof, etc.), antitumorantibiotics (e.g., mitomycin, adriamycin, etc.), plant-derived antitumoragents (e.g., vincristine, vindesine, taxol, etc.), cisplatin,carboplatin, etopoxide and the like, among those preferably,5-fluorouracil derivatives such as Furtulon and Neo-Furtulon.

Examples of the immunotherapeutic agent include microorganism- orbacterium-derived components (e.g., muramyl dipeptide derivatives,Picibanil, etc.), immunopotentiator polysaccharides (e.g., lentinan,schizophyllan, krestin, etc.), genetically engineered cytokines (e.g.,interferons, interleukins (IL), etc.), colony stimulating agents (e.g.,granulocyte colony stimulating factor, erythropoietin, etc.) and thelike, among those preferably, interleukins such as IL-1, IL-2, IL-12 andthe like.

The anti-thrombic agent includes, for example, heparin (e.g., heparinsodium, heparin calcium, dalteparin sodium and the like), warfarin(e.g., warfarin potassium and the like), anti-thrombin agents (e.g.,argatroban and the like), thrombolytic agents (e.g., urokinase,tisokinase, alteplase, nateplase, monteplase, pamiteplase and the like),platelet aggregation inhibitors (e.g., ticlopidine hydrochloride,cilostazol, ethyl eicosapentaenoic acid, beraprost sodium, sarpogrelatehydrochloride and the like) and the like.

The agents of ameliorating cachexia include, for example, cyclooxygenaseinhibitors (e.g., indomethacin, etc.) (Cancer Research, vol. 49, pp.5935-5939, 1989), progesterone derivatives (e.g., megestrol acetate)(Journal of Clinical Oncology, vol. 12, pp. 213-225, 1994),glucocorticoids (e.g. dexamethasone, etc.), metoclopramidepharmaceuticals, tetrahydrocannabinol pharmaceuticals (the abovereferences are applied to both), fat metabolism ameliorating agents(e.g., eicosapentanoic acid, etc.) (British Journal of Cancer, vol. 68,pp. 314-318, 1993), growth hormones, IGF-1, and antibodies to thecachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M, can also beused as the combination drug.

Furthermore, the combination drug includes neuranagenesis promoters(e.g., Y-128, VX-853, prosaptide, etc.), antidepressants (e.g.,desipramine, amitriptyline, imipramine, etc.), antiepileptics (e.g.,lamotrigine, etc.), antiarrhythmic drug (e.g., mexiletine, etc.),acetylcholine receptor ligands (e.g., ABT-594, etc.), endothelinreceptor antagonists (e.g., ABT-627, etc.), monoamine uptake inhibitor(e.g., tramadol, etc.), narcotic analgesics (e.g., morphine, etc.), GABAreceptor agonists (e.g., gabapentin, etc.), α2 receptor agonists (e.g.,clonidine, etc.), local analgesics (e.g., capsaicin, etc.), proteinkinase C inhibitors (e.g., LY-333531, etc.), antianxiety drugs (e.g.,benzodiazepine, etc.), phosphodiesterase inhibitors (e.g., sildenafil(citrate), etc.), dopamine agonists (e.g., apomorphine, etc.),therapeutic agents for osteoporosis (e.g., alfacalcidol, calcitriol,elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronatedisodium, alendronate sodium hydrate, incadronate disodium, etc.),antidementia agents (e.g., tacrine, donepezil, rivastigmine,galantamine, etc.), therapeutic agents for incontinentia or pollakiuria(e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverinehydrochloride, etc.) midazolam, ketoconazole and the like.

When the compound of the present invention is applied to theabove-mentioned diseases, it can be used in combination with biologicalpreparations (e.g.: antibody, vaccine preparations and the like), and itis also possible to apply as a combination therapy by combining with agene therapy method and the like. The antibody and vaccine preparationinclude, for example, vaccine preparations for angiotensin II, vaccinepreparations for CETP, CETP antibody, TNFα antibody and antibody forother cytokines, amyloid β vaccine preparations, diabetes mellitus Ivaccines (DIAPEP-277 of Peptor Corp. and the like) and the like, as wellas antibody or vaccine preparation for cytokine, renin-angiotensinenzymes and the products thereof, antibody or vaccine preparation forenzyme or protein involved blood lipid metabolism, antibody or vaccinerelated to enzyme and protein involved in blood coagulation-fibrinolyticsystem, antibody or vaccine preparation for protein involved in glucosemetabolism and insulin resistance and the like. The gene therapy methodincludes, for example, a therapy method using gene related to cytokine,rennin-angiotensin enzymes and products thereof, a therapy method usingDNA decoys such as NFκB decoy and the like, a therapy method usingantisense, a therapy method using a gene related to the enzyme andprotein involved blood lipid metabolism (e.g., gene relating formetabolism, excretion and absorption of cholesterol or triglyceride orHDL cholesterol or blood phospholipid and the like), a therapy methodusing a gene related to enzyme and protein (e.g., growth factors such asHGF, VEGF, etc., and the like) involved in angiogenesis therapytargeting peripheral vascular obstruction and the like, a therapy methodusing a gene related to protein involved in glucose metabolism andinsulin resistance, antisense for cytokines such as TNF and the like,and the like. It is also possible to use concurrently with variousregeneration methods of organs such as heart regeneration, renalregeneration, pancreatic regeneration, revascularization and the like,and angiogenesis therapy utilizing transplantation of bone marrow cells(bone marrow mononuclear cells, bone marrow stem cells and the like).

In the following, methods of producing Compound (I) will be explained indetail.

Compound (I) can be prepared by a per se known method, for example,Methods A to Bb or a method analogous thereto shown below. The amount ofthe solvent to be used in the preparation is not limited as long as themixture can be stirred. In each of the following production methods, thestarting compound may be used in the form of a salt, and such saltincludes those exemplified as the salt of the aforementioned Compound(I).

[Method A]

Compound (I-1) which is Compound (I) of the present invention wherein R¹is a hydrogen atom can be synthesized, for example, by the followingmethod and the like.

[wherein R¹′ is an optionally substituted hydrocarbon group, and theother symbols are as defined above.]

The “optionally substituted hydrocarbon group” in R¹, has the samemeaning as the above-mentioned “optionally substituted hydrocarbongroup” in R¹, preferably a C₁₋₆ alkyl group, further preferably, methyl,ethyl and the like.

In this method, Compound (I-2) is hydrolyzed to give Compound (I-1).This reaction is carried out in the presence of an acid or base in asuitable solvent according to a conventional method.

The acid includes, for example, inorganic acid such as hydrochloricacid, sulfuric acid, hydrobromic acid and the like; organic acid such asacetic acid and the like, and the like. The base includes, for example,alkali metal carbonate such as potassium carbonate, sodium carbonate andthe like; alkali metal alkoxide such as sodium methoxide and the like;alkali metal hydroxide such as potassium hydroxide, sodium hydroxide,lithium hydroxide and the like, and the like. The amount of the acid andbase is usually excessive amount relative to Compound (I-2). The amountof the acid is preferably about 2 to about 50 equivalents relative toCompound (I-2), and the amount of the base is about 1.2 to about 5equivalents relative to Compound (I-2).

The suitable solvent includes, for example, alcohols such as methanol,ethanol and the like; ethers such as tetrahydrofuran, dioxane, diethylether and the like; dimethylsulfoxide; acetone and water and the like.Such solvent may be mixed in a suitable ratio.

The reaction temperature is usually about −20 to about 150° C.,preferably about −10 to about 100° C. The reaction time is usually about0.1 to about 20 hours.

[Method B]

Compound (I-3) which is Compound (I) of the present invention wherein Yis —SO_(m)— (m is 1 or 2) can be synthesized, for example, by thefollowing method and the like.

[wherein the symbols are as defined above.]

In this method, Compound (I-4) is oxidized to give Compound (I-3). Thisreaction is usually carried out using an oxidizing agent in a solventwhich does not interfere with the reaction solvent.

The oxidizing agent includes, for example, 3-chlorophenylperbenzoicacid, sodium periodate, hydrogen peroxide water, peracetic acid and thelike. The amount of the oxidizing agent is about 1 equivalent toexcessive amount, preferably about 1 to about 10 equivalents relative toCompound (I-4).

The reaction solvent which does not interfere with the reactionincludes, for example, ethers such as diethyl ether, tetrahydrofuran,dioxane and the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; amides such as N,N-dimethylformamide andthe like; alcohols such as ethanol, methanol and the like, and the like.Such solvent may be mixed in a suitable ratio.

The reaction temperature is usually about −50 to about 150° C.,preferably about −10 to about 100° C. The reaction time is usually about0.5 to about 20 hours.

[Method C]

Compound (I-5) which is Compound (I) of the present invention wherein X²is —SO_(n)— (n is 1 or 2) can be synthesized, for example, by thefollowing method and the like.

[wherein the symbols are as defined above.]

In this method, Compound (I-6) is oxidized to give Compound (I-5). Thepresent method is carried out, for example, under the same reactionconditions as those of the conversion from Compound (I-4) to Compound(I-3) in the above-mentioned Method B.

[Method D]

Compound (I-7) which is Compound (I) of the present invention wherein Yis —O— or —S— and M² is not a bond can be synthesized, for example, bythe following method and the like.

[wherein Y′ is —O— or —S—, M^(2a) is an optionally substituted divalentaliphatic hydrocarbon group, E is halogen such as a chlorine atom,bromine atom, iodine atom and the like, a leaving group such asmethanesulfonyloxy, p-toluenesulfonyloxy and the like, and the othersymbols are as defined above.]

The “optionally substituted divalent aliphatic hydrocarbon group” inM^(2a) has the same meaning as the above-mentioned “optionallysubstituted divalent aliphatic hydrocarbon group” in M².

In this method, Compound (II) is reacted with Compound (III) to giveCompound (I-7). This reaction is carried out according to a conventionalmethod in the presence of a base in a reaction solvent which does notinterfere with the reaction.

The base includes, for example, alkali metal carbonate such as potassiumcarbonate, sodium carbonate and the like; alkali metal hydrogencarbonate such as potassium hydrogen carbonate, sodium hydrogencarbonate and the like; alkali metal hydroxide such as potassiumhydroxide, sodium hydroxide, lithium hydroxide and the like; amines suchas pyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene and the like; metal hydride such aspotassium hydride, sodium hydride and the like; alkali metal alkoxidesuch as sodium methoxide, sodium ethoxide, potassium tert-butoxide andthe like. The amount of such base is preferably about 1 to about 5 molarequivalents relative to Compound (II).

The reaction solvent which does not interfere with the reactionincludes, for example, aromatic hydrocarbons such as benzene, toluene,xylene and the like; ethers such as tetrahydrofuran, dioxane, diethylether and the like; ketones such as acetone, 2-butanone and the like;halogenated hydrocarbons such as chloroform, dichloromethane and thelike; amides such as N,N-dimethylformamide and the like; sulfoxides suchas dimethylsulfoxide and the like, and the like. Such solvent may bemixed in a suitable ratio.

The reaction temperature is usually about −50 to about 150° C.,preferably about −10 to about 100° C. The reaction time is usually about0.5 to about 20 hours.

[Method E]

Compound (I-9) which is Compound (I) of the present invention wherein Yis —O— or —S—, M¹ is an optionally substituted divalent aliphatichydrocarbon group can be synthesized, for example, by the followingmethod and the like.

[wherein M^(1a) is an optionally substituted divalent aliphatichydrocarbon group, and the other symbols are as defined above.]

The “optionally substituted divalent aliphatic hydrocarbon group” inM^(1a) has the same meaning as the above-mentioned “optionallysubstituted divalent aliphatic hydrocarbon group” in M¹.

In this method, Compound (V) is reacted with Compound (IV) to giveCompound (I-9). The present method is carried out for example under thesame reaction conditions as those of the above-mentioned Method D byreacting Compound (II) with Compound (III) to give compound (1-7).

[Method F]

Compound (I-8) which is Compound (I) of the present invention wherein Yis —O— or —S—, and M² is a bond can be synthesized, for example, by thefollowing method and the like.

[wherein the symbols are as defined above.]

In this method, Compound (II-1) is reacted with Compound (IV-1) to giveCompound (I-8). This reaction is carried out according to the methodknown per se, which is known as a so called ester interchange reaction,such as the method described in Synthesis, page 1 (1981), or a methodanalogous thereto. That is, this reaction is generally carried out inthe presence of an organic phosphorus compound and electrophile in asolvent that does not adversely affect the reaction.

The organic phosphorus compound includes, for example,triphenylphosphine, tributylphosphine and the like. The electrophileincludes, for example, diethyl azodicarboxylate, diisopropylazodicarboxylate, azodicarbonyldipiperazine,1,1′-(azodicarbonyl)dipiperidine and the like. The amount of the organicphosphorus compound and the electrophile is preferably about 1 to about5 molar equivalents, respectively relative to Compound (II-1).

The reaction solvent which does not interfere with the reactionincludes, for example, ethers such as diethyl ether, tetrahydrofuran,dioxane and the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; amides such as N,N-dimethylformamide andthe like; sulfoxides such as dimethylsulfoxide and the like, and thelike. Such solvent may be mixed in a suitable ratio.

The reaction temperature is usually about −50 to about 150° C.,preferably about −10 to about 100° C. The reaction time is usually about0.5 to about 20 hours.

[Method G]

Compound (I-10) which is Compound (I) of the present invention wherein Yis —CON(R³)— (provided that the carbonyl carbon atom is bonded to M¹)can be synthesized, for example, by the following method and the like.

[wherein the symbols are as defined above.]

This method is a method of condensing (amidation) Compound (VI) withCompound (VII) to give Compound (I-10). This reaction is carried out bya per se known method, for example,

(1) a method of directly condensing Compound (VI) and Compound (VII)with a condensing agent, or

(2) a method of reacting suitably a reactive derivative of Compound (VI)and Compound (VII) and the like.

Firstly, the method (1) will be explained.

The above-mentioned condensing agent includes generally known condensingagent, for example, a carbodiimide-based condensing reagent such asdicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydrochloride thereofand the like; a phosphate-based condensing reagent such as diethylcyanophosphate, diphenylphosphoryl azide and the like;carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborateand the like.

The method (1) is usually carried out in a solvent, and the solventincludes, for example, amides such as N,N-dimethylformamide,N,N-dimethylacetoamide and the like; halogenated hydrocarbons such aschloroform, dichloromethane and the like; aromatic hydrocarbons such asbenzene, toluene and the like; ethers such as tetrahydrofuran, dioxane,diethyl ether and the like; ethyl acetate, water and the like. Suchsolvent may be mixed in a suitable ratio.

The amount of Compound (VII) is 0.1 to 10 molar equivalents, preferably0.3 to 3 molar equivalents relative to Compound (VI).

The amount of the condensing agent is 0.1 to 10 molar equivalents,preferably 0.3 to 3 molar equivalents relative to Compound (VI).

When carbodiimide-based condensing reagent such asdicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydrochloride thereofand the like is used as the condensing agent, if necessary, suitablecondensing promoter (e.g., 1-hydroxy-7-azabenzotriazole,1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide andthe like) may be used. Furthermore, when phosphate-based condensingreagent such as diethyl cyanophosphate, diphenylphosphoryl azide and thelike is used as the condensing agent, organic amine base such astriethylamine and the like may be also added.

The amount of the above-mentioned condensing promoter or organic aminebase is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molarequivalents relative to Compound (VI).

The reaction temperature is usually −30° C. to 100° C. The reaction timeis usually 0.5 to 60 hours.

In the following, the method (2) will be explained.

The reactive derivative of Compound (VI) includes, for example, acidanhydride, acid halide (e.g., acid chloride, acid bromide), acidimidazolide, active ester (for example, phenyl ester, nitro-orhalogen-substituted phenyl ester (for example, 4-nitrophenyl ester,pentafluorophenyl ester and the like), 1-hydroxy-7-azabenzotriazoleester, 1-hydroxybenzotriazole ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester and the like), or mixed acid anhydride (forexample, anhydride with methyl carbonate, ethyl carbonate, isobutylcarbonate and the like) and the like.

For example, when acid anhydride, acid halide, acid imidazolide oractive ester is used as the above-mentioned reactive derivative, thereaction is carried out in the presence or absence of a base in areaction solvent which does not interfere with the reaction.

The base includes, for example, amines such as triethylamine,N-methylmorpholine, N,N-dimethylaniline and the like; alkali metalcarbonate such as potassium carbonate, sodium carbonate and the like;alkali metal hydrogen carbonate such as potassium hydrogen carbonate,sodium hydrogen carbonate and the like; alkali metal hydroxide such aspotassium hydroxide, sodium hydroxide, lithium hydroxide and the like;and the like. The amount of the base is 0.1 to 10 molar equivalents,preferably 0.3 to 3 molar equivalents relative to Compound (VI) or areactive derivative thereof.

The reaction solvent which does not interfere with the reactionincludes, for example, halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene and the like; ethers such as tetrahydrofuran, dioxane, diethylether and the like; ethyl acetate, water, N,N-dimethylformamide and thelike. Such solvent may be mixed in a suitable ratio.

The amount of Compound (VII) is 0.1 to 10 molar equivalents, preferably0.3 to 3 molar equivalents relative to Compound (VI) or a reactivederivative thereof.

The reaction temperature is usually −30° C. to 100° C. The reaction timeis usually 0.5 to 20 hours.

Furthermore, when the mixed acid anhydride is used, Compound (VI) isreacted with chlorocarbonate ester (e.g., methyl chlorocarbonate, ethylchlorocarbonate, isobutyl chlorocarbonate and the like) in the presenceof a base (e.g., amines such as triethylamine, N-methylmorpholine,N,N-dimethylaniline and the like; alkali metal carbonate such aspotassium carbonate, sodium carbonate and the like; alkali metalhydrogen carbonate such as potassium hydrogen carbonate, sodium hydrogencarbonate and the like; alkali metal hydroxide such as potassiumhydroxide, sodium hydroxide, lithium hydroxide and the like, and thelike), and further with Compound (VII).

The amount of Compound (VII) is usually 0.1 to 10 molar equivalents,preferably 0.3 to 3 molar equivalents relative to Compound (VI) or mixedacid anhydride thereof.

The reaction temperature is usually −30° C. to 100° C. The reaction timeis usually 0.5 to 20 hours.

[Method H]

Compound (I-11) which is Compound (I) of the present invention wherein Yis —N(R³)CO— (provided that the carbonyl carbon is bonded to M²) can besynthesized, for example, by the following method and the like.

[wherein the symbols are as defined above.]

This method is a method of condensing (amidation) Compound (VIII) withCompound (IX) to give Compound (I-11). The present method is carriedout, for example, under the same reaction conditions as those of theabove-mentioned Method G by reacting Compound (VI) with Compound (VII)to give Compound (I-10).

[Method I-1] [Method I-2]

Compounds (I-12a′), (I-12b′), (I-12a) and (I-12b) which are Compound (I)of the present invention wherein Y is a bond, and M¹ is an optionallysubstituted divalent aliphatic hydrocarbon group having 2 or more carbonatoms can be synthesized, for example, by the following methods (I-1)and (I-2) and the like.

[wherein Q is P(O) (OR⁷)₂ or PR⁷ ₃ (wherein R⁷ is a C₁₋₄ alkyl group(for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl and the like) or a C₆₋₁₀ aryl group (for example,phenyl, naphthyl and the like) optionally substituted with a C₁₋₄ alkylgroup, preferably methyl, ethyl, phenyl and the like.), M^(1b) is a bondor an optionally substituted divalent aliphatic hydrocarbon group,R^(8a), R^(8b), R^(9a) and R^(9b) may be the same or different and areeach independently a substituent suitably selected from a hydrogen atom,an alkyl group or the substituent which the “divalent aliphatichydrocarbon group” in the above-mentioned M¹ may have, and the othersymbols are as defined above.]

The “optionally substituted divalent aliphatic hydrocarbon group” inM^(1b) is has the same meaning as the above-mentioned “optionallysubstituted divalent aliphatic hydrocarbon group” in the M¹. The “alkylgroup f in R^(8a), R^(8b), R^(9a) and R^(9b) is straight or branchedalkyl group, and the number of the carbon atoms is not particularlylimited, preferably less than 18, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

[Process 1a] Preparation of Compound (I-12a′)

Compound (I-12a′) is obtained by reacting Compound (XI) (1) withphosphonium ylide induced from phosphonium salt (X) (Q=PR⁷ ₃) to giveolefin, which is so-called Wittig reaction, or

(2) with phosphonate carboanion induced from alkylphosphorous diester(X) (Q=P(O) (OR⁷)₂) to give olefin, which is so-calledWittig-Horner-Emmons reaction.

[Process 1b] Preparation of Compound (I-12b′)

Compound (I-12b′) is obtained by reacting Compound (XII)

(1) with phosphonium ylide induced from phosphonium salt (XIII) (Q=PR⁷₃) to give olefin, which is so-called Wittig reaction, or

(2) with phosphonate carboanion induced from alkylphosphorous diester(XIII) (Q=P(O) (OR⁷)₂) to give olefin, which is so-calledWittig-Horner-Emmons reaction.

The reaction is known per se, and can be carried out according to or byreferring to the conditions described or cited in, for example, 4th ed.Jikken Kagaku Koza (Maruzen) vol. 19, Organic Synthesis I, pp. 57-78.

[Process 2a] Preparation of Compound (I-12a)

The double bond of Compound (I-12a′) obtained in Process 1a is reducedto give Compound (I-12a).

[Process 2b] Preparation of Compound (I-12b)

The double bond of Compound (I-12b′) obtained in Process 1b is reducedto give Compound (I-12b).

In such reduction reaction, catalytic hydrogenation and the like can beused in the presence of a catalyst.

The catalyst to be used for catalytic hydrogenation, includes metalssuch as palladium, platinum, nickel, rhodium and the like, oxides, saltsand complexes of thereof, and the like. These catalysts can be also usedby being carried on various carriers such as carbon and the like. Thehydrogenation can be conducted under normal pressure or underpressurization.

The solvent to be used therefor can be appropriately determined, forexample, alcohols (for example, methanol or ethanol and the like),ethers (for example, tetrahydrofuran, dioxane, diethyl ether and thelike), hydrocarbons (for example, hexane, pentane and the like),aromatic hydrocarbons (for example, benzene, toluene and the like),halogenated hydrocarbon (for example, dichloromethane, chloroform andthe like), esters (for example, ethyl acetate and the like), aproticpolar solvent (for example, N,N-dimethylformamide, dimethylsulfoxide,acetonitrile and the like) and the like. Such solvent may be mixed in asuitable ratio.

The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. Thereaction temperature is from −100 to 100° C. (preferably from −70 to 50°C.).

Compound (I-2) which is used as a starting compound in Method A isprepared by, for example, the above-mentioned Method B to Method I.

Compound (I-4) which is used as a starting compound in Method B isprepared, for example, by the above-mentioned Method A or Method C toMethod F.

Compound (I-6) which is used as a starting compound in Method C isprepared, for example, by the above-mentioned Method A, Method B orMethod D to Method I.

Compound (II-1′) which is Compound (II) wherein Y is —O— and the moietyadjacent to Y′ of M¹ is non-substituted methylene (also including acompound of Compound (II-1) wherein the moiety adjacent to OH group ofM^(1a) a is non-substituted methylene, and used as a starting compoundin Method F, and a compound of Compound (II-1″) wherein R⁸ is a hydrogenatom, and used as a starting compound In the below-described Method P),and used as a starting compound in Method D is prepared, for example, bythe following Method J.

[Method J]

[wherein R¹⁰ is a hydrogen atom or an optionally substituted hydrocarbongroup, and the other symbols are as defined above.]

Herein, the “optionally substituted hydrocarbon group” represented bythe above-mentioned R¹⁰ includes those exemplified as theabove-mentioned R¹.

In this method, Compound (XIV) is reduced to give Compound (II-1′).

In this reduction reaction, the reducing agent is used in an amount of 1equivalent to large excess (preferably 1 to 10 equivalents) relative toCompound (XIV). The reducing agent includes, for example, metal hydrogencomplex compound such as sodium borohydride, sodium cyanoborohydride,aluminium lithium hydride, diisobutylaluminium hydride and the like ordiborane and the like.

Method J is usually carried out in a solvent. The solvent to be usedtherefor can be appropriately determined depending on the kind of thereducing agent, for example, alcohols (for example, methanol or ethanoland the like), ethers (for example, tetrahydrofuran, dioxane, diethylether and the like), hydrocarbons (for example, hexane, pentane and thelike), aromatic hydrocarbons (for example, benzene, toluene and thelike), halogenated hydrocarbon (for example, dichloromethane, chloroformand the like), aprotic polar solvent (for example,N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like) andthe like. The reaction time is 0.5 to 72 hours, preferably 1 to 24hours. The reaction temperature is −30 to 100° C.

Compound (II-2) which is Compound (II) wherein Y′ is —S—, and used as astarting compound in Method D is prepared, for example, by the followingMethod K.

[Method K]

[wherein R″ is an optionally substituted hydrocarbon group, and theother symbols are as defined above.]

The “optionally substituted hydrocarbon group” in R¹¹ has the samemeaning as the above-mentioned “optionally substituted hydrocarbongroup” in R¹, preferably a C₁₋₄ alkyl group, or a phenyl groupoptionally substituted with a C₁₋₄ alkyl group or 1 to 3 halogen atomsand the like.

[Process 1]

In this method, Compound (II-1) is reacted with Compound (XV) to giveCompound (II-2′). This reaction is carried out in the same manner as inthat of Compound (II-1) and Compound (IV-1) in the above-mentionedMethod F.

Compound (XV) can be prepared by a per se known method, or is availableas a commercial product.

[Process 2]

In this method, Compound (II-2′) obtained in Process 1 is hydrolyzed togive Compound (II-2). This reaction is carried out in the same manner asthe preparation of Compound (I-1) by hydrolyzing Compound (I-2) in theabove-mentioned Method A.

Moreover, Compound (II-2) may be separated and purified as thiol, and ifthe above-mentioned hydrolyzation is carried out in the presence of abase, it may be separated and purified as alkyl metal thiolate, orwithout separating alkylmetal thiolate, it may be used in thepreparation of Compound (I-7) shown in Method D.

Compound (V) which is used as a starting compound in Method E isprepared, for example, by the following Method L.

[Method L]

[wherein the symbols are as defined above.]

The reaction of converting the hydroxy group of Compound (II-1) to aleaving group E is carried out by, for example, the reaction of Compound(II-1) and a halogenating agent when E is halogen. The halogenatingagent includes, for example, phosphorus halide such as phosphorustrichloride, phosphorus oxychloride, phosphorus pentachloride,phosphorus tribromide and the like, red phosphorus and halogen orthionyl chloride and the like. The amount of the halogenating agent is 1to 5 equivalents to 1 equivalent of Compound (II-1).

When E is sulfonyloxy such as toluenesulfonyloxy or methanesulfonyloxyand the like, it is carried out by the reaction of Compound (II-1) and asulfonylating agent. The sulfonylating agent includes, for example,corresponding sulfonyl chloride or sulfonic acid anhydride (for example,toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic acidanhydride and the like) and the like. The amount of the sulfonylatingagent is 1 to 5 equivalents to 1 equivalent of Compound (II-1). Aninorganic base such as potassium carbonate, sodium hydrogen carbonateand the like, or organic base such as 4-(N,N-dimethylamino)pyridine,triethylamine, pyridine, dimethylaniline, 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like may be also used in 1 to 10 equivalents.

Method E is usually carried out in a solvent. The solvent to beconveniently used therefor includes, for example, halogenatedhydrocarbons (for example, dichloromethane, chloroform, dichloroethaneand the like), hydrocarbons (for example, hexane, pentane and the like),aromatic hydrocarbons (for example, benzene, toluene and the like),ethers (for example, diethyl ether, tetrahydrofuran and the like),esters (for example, methyl acetate, ethyl acetate and the like),aprotic polar solvent (for example, N,N-dimethylformamide,dimethylsulfoxide, acetonitrile and the like) and the like.

The reaction temperature is −30° C. to 100° C., preferably −10° C. to50° C. The reaction time is usually 10 minutes to 100 hours, preferably3 to 24 hours.

Compound (VI) which is used as a starting compound in Method G isprepared, for example, by the following Method M.

[Method M]

[wherein R¹⁰′ is an optionally substituted hydrocarbon group, and theother symbols are as defined above.]

The “optionally substituted hydrocarbon group” in R¹⁰′ has the samemeaning as the above-mentioned “optionally substituted hydrocarbongroup” in R¹.

In this method, Compound (XIV′) is hydrolyzed to give Compound (VI).This reaction is carried out in the same manner as the preparation ofCompound (I-1) by hydrolyzing Compound (I-2) in the above-mentionedMethod A.

Compound (VIII) which is used as a starting compound in Method H isprepared, for example, by the following Method N-1 or Method N-2.

[Method N-1]

[wherein the symbols are as defined above.]

In this method, Compound (V) is reacted with Compound (XVI) to giveCompound (VIII). This reaction is carried out in the same manner as thatof Compound (II) with Compound (III) in the above-mentioned Method D.

[Method N-2]

[wherein the symbols are as defined above.]

The present method is a method of reacting Compound (XII) with ammoniaor primary amine (XVI), and reducing the produced imine or iminium ionto synthesize amines, i.e., a method of obtaining Compound (VIII′) byso-called reductive amination reaction.

In this reaction, ammonia or primary amine (XVI) is used in 1 equivalentor large excess (preferably 1 to 10 equivalents) relative to Compound(XII).

An acid (for example, mineral acid such as hydrochloric acid, phosphoricacid, sulfuric acid and the like or organic acid such as toluenesulfonicacid, methanesulfonic acid, acetic acid and the like) may be added in0.1 to 2 equivalents. The reduction method includes reduction with areducing agent such as metal hydrogen complex compound such as sodiumborohydride, sodium cyanoborohydride, aluminium lithium hydride and thelike, diborane and the like, catalytic hydrogenation in the presence ofa catalyst such as palladium or Raney nickel and the like, electrolyticreduction using lead or platinum as a negative electrode. The reducingagent is used in 1 equivalent to large excess (preferably 1 to 10equivalents).

Method N-2 is usually carried out in a solvent. The solvent to be usedtherefor can be appropriately determined depending on methods ofreducing, for example, alcohols (for example, methanol or ethanol andthe like), ethers (for example, tetrahydrofuran, dioxane, diethyl etherand the like), halogenated hydrocarbon (for example, dichloromethane,chloroform and the like), hydrocarbons (for example, hexane, pentane andthe like), aromatic hydrocarbons (for example, benzene, toluene and thelike), aprotic polar solvent (for example, N,N-dimethylformamide,dimethylsulfoxide, acetonitrile and the like) and the like. The reactiontime is 0.5 to 72 hours, preferably 1 to 24 hours. The reactiontemperature is −30° C. to 100° C., preferably 0° C. to 60° C.

Compound (XVI) can be prepared by a per se known method, or is availableas a commercial product.

Compound (X) which is used as a starting compound in Method I-1 isprepared, for example, by the following Method O.

[Method O]

[wherein the symbols are as defined above.]

This reaction is a method of reacting Compound (V′) with Compound (XVII)when Q is P(O)(OR⁷)₂ in Compound (X), or reacting Compound (V′) withCompound (XVIII) when Q is PR⁷ ₃ in Compound (X), to produce Compound(X).

In this reaction, Compound (XVII) or Compound (XVIII) is used in 1equivalent or large excess (preferably 1 to 10 equivalents) relative toCompound (V′).

The reaction can be carried out without solvent, or in a solventsuitably selected from, for example, ethers (for example,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbon (for example, dichloromethane, chloroform and the like),hydrocarbons (for example, hexane, pentane and the like), aromatichydrocarbons (for example, benzene, toluene and the like), aprotic polarsolvent (for example, N,N-dimethylformamide, dimethylsulfoxide,acetonitrile and the like) and the like.

The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. Thereaction temperature is 0° C. to 20° C.

Compound (XVII) and (XVIII) can be prepared by a per se known method, oris available as a commercial product. Furthermore, Compound (V′) isprepared by the above-mentioned Method L.

Compound (XII) which is used as a starting compound in Method I-2 isprepared, for example, by the following Method P.

[Method P]

[wherein the symbols are as defined above.]

In this method, Compound (II-1″) is oxidized to give Compound (XII).

In the oxidation reaction, an oxidizing agent is used, for example, in 1equivalent to 20 equivalents relative to Compound (II-1″). The oxidizingagent includes activated manganese dioxide, pyridinium chlorochromate(PCC), pyridinium dichromate (PDC), dimethylsulfoxide-acid anhydride(acetic anhydride, trifluoroacetic anhydride and the like),dimethylsulfoxide-thionyl chloride, dimethylsulfoxide-sulfuryl chloride,dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-chlorine, anddimethylsulfoxide-dicyclohexylcarbodiimide (DCC) in the presence of acid(phosphoric acid, trifluoroacetic acid, dichloroacetic acid and thelike) and the like.

The oxidation reaction is usually carried out in a solvent. The solventto be used therefor is can be appropriately determined depending on thekind of the oxidizing agent, for example, ethers (for example,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbon (for example, dichloromethane, chloroform and the like),ketones (for example, acetone, methyl ethyl ketone and the like),aprotic polar solvent (for example, N,N-dimethylformamide,dimethylsulfoxide, acetonitrile and the like) and the like.

The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. Thereaction temperature is appropriately determined depending on the kindof an oxidizing agent, and is −80 to 100° C.

Compound (II-2) which is Compound (II-1″) wherein R⁸ is not a hydrogenatom, and used as a starting compound in Method P is prepared, forexample, by the following Method P′.

[Method P′]

[wherein R^(8a) is an optionally substituted hydrocarbon group, M is ahydrogen atom or metal atom such as sodium, lithium, magnesium and thelike (in the case of a divalent metal, the remaining monovalent may beoccupied by halogen atom and the like), and the other symbols are asdefined above.]

The “optionally substituted hydrocarbon group” in R^(8a) has the samemeaning as the above-mentioned “optionally substituted hydrocarbongroup” in R¹.

In this method, Compound (XII-1) is reacted with R^(8a)-M to giveCompound (II-2). This reaction is in accordance with a conventionalmethod in a reaction solvent which does not interfere with the reaction.R^(8a)-M is used in 1 equivalent or large excess, preferably about 1 toabout 5 molar equivalents relative to Compound (XII-1). When M is ahydrogen atom, the reaction is carried out in the presence of a basiccompound. The basic compound to be used includes inorganic basiccompounds such as sodium hydroxide and potassium carbonate, alkoxidessuch as sodium methoxide and potassium tert-butoxide, organic lithiumreagents such as n-butyl lithium, phenyl lithium and lithiumdiisopropylamide, alkyl metal amides such as sodium amide and the like.

The reaction solvent which does not interfere with the reactionincludes, for example, hydrocarbons such as pentane, hexane and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such asdimethylsulfoxide and the like, and the like. Such solvent may be mixedin a suitable ratio.

Moreover, Compound (II-1′) is oxidized to give Compound (XII-1) in theabove-mentioned Method P.

Compound (VI′) which is Compound (VI) wherein M¹ is an optionallysubstituted divalent aliphatic hydrocarbon group, and used as a startingcompound in Method G or, Compound (VI′) which is Compound (XIV) whereinM¹ is an optionally substituted divalent aliphatic hydrocarbon group,and R¹⁰ is hydrogen, and used as a starting compound in Method J, isprepared, for example, by the following Method Q.

[Method Q]

[wherein the symbols are as defined above.][Process 1-a]

In this method, Compound (V) is reacted with inorganic cyanide to giveCompound (XIX). This reaction is carried out according to a conventionalmethod in a reaction solvent which does not interfere with the reaction.

The inorganic cyanide to be used includes, for example, cyanide sodium,cyanide potassium, cyanide copper (I) and the like. The amount of suchinorganic cyanide is preferably 1 equivalent to large excess (preferably1 to 10 equivalents) relative to Compound (V).

Furthermore, for the reaction, alkali metal iodide such as iodide sodiumand the like may be added in 1 equivalent or large excess (preferably 1to 10 equivalents) as a reaction promoter.

The reaction solvent which does not interfere with the reactionincludes, for example, water, alcohols (for example, methanol or ethanoland the like), ethers (for example, tetrahydrofuran, dioxane, diethylether and the like), halogenated hydrocarbon (for example,dichloromethane, chloroform and the like), hydrocarbons (for example,hexane, pentane and the like), aromatic hydrocarbons (for example,benzene, toluene and the like), aprotic polar solvent (for example,N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like) andthe like. Such solvent may be mixed in a suitable ratio. The reactiontemperature is usually about 0° C. to about 200° C. The reaction time isusually about 0.5 to about 20 hours.

[Process 1-b]

In this method, Compound (II-1) is reacted with hydrogen cyanide byso-called Mitsunobu reaction to give Compound (XIX). This reactioncarried out in the same manner as the preparation of Compound (I-8) byreacting Compound (II-1) with Compound (IV-1) in the above-mentionedMethod F.

Moreover, in the above-mentioned reaction, cyanohydrin (for example,acetonecyanohydrin and the like) may be used as hydrogen cyanide sourceinstead of hydrogen cyanide.

[Process 2]

In this method, Compound (XIX) obtained in Process 1-a or Process 1-b ishydrolyzed to give Compound (VI′). This reaction is carried out in thesame manner as the preparation of Compound (I-1) by hydrolyzing Compound(I-2) in the above-mentioned Method A.

Compound (XXI) and Compound (XIV″) which is Compound (XIV) in Method J(also including Compound (XIV′) which is used as a starting compound inMethod M) wherein M¹ is optionally substituted divalent aliphatichydrocarbon group having 2 or more, is prepared, for example, by thefollowing Method R.

[Method R]

[wherein R¹² is a substituent suitably selected from a hydrogen atom, analkyl group or the substituent which the “divalent aliphatic hydrocarbongroup” may have in the above-mentioned M¹, and the other symbols are asdefined above.]

The alkyl group in R¹² is straight or branched alkyl group, and thenumber of carbon atoms is not particularly limited, preferably less than18, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl and the like.

[Process 1] Preparation of Compound (XXI)

Compound (XXI) is obtained by reacting Compound (XII) (1) withphosphonium ylide induced from phosphonium salt (XX) (Q=PR⁷ ₃) to giveolefin, which is so-called Wittig reaction, or

(2) with phosphonate carboanion induced from alkylphosphorous diester(XX) (Q=P(O) (OR⁷)₂) to give olefin, which is so-calledWittig-Horner-Emmons reaction.

This reaction is carried out in the same manner as the preparation ofCompound (I-12a′) by Wittig reaction or Wittig-Horner-Emmons reaction inthe above-mentioned [Process 1a] of Method I-1.

Compound (XX) is can be prepared by a per se known method or a methodanalogous thereto, or is available as a commercial product.

[Process 2] Preparation of Compound (XIV″)

This reaction is a method of reducing the double bond of Compound (XXI)obtained in Process 1 to give Compound (XIV″). This reaction is carriedout in the same manner as the preparation of Compound (I-12a) byhydrogenation of Compound (I-12a′) in [Process 2a] of theabove-mentioned Method I.

Compound (III) in Method D is prepared, for example, by the followingMethod S.

[Method S]

[wherein the symbols are as defined above.]

In this method, the hydroxy group of Compound (IV-2) is converted to aleaving group E to give Compound (III). This reaction is carried out inthe same manner as the preparation of Compound (V) by converting thehydroxy group of Compound (II-1) to a leaving group E in theabove-mentioned Method L.

Compound (XI) in Method I-1 is prepared, for example, by the followingMethod T.

[Method T]

[wherein the symbols are as defined above.]

In this method, Compound (IV-3) is oxidized to give Compound (XI). Thisreaction is carried out in the same manner as the preparation ofCompound (XII) by oxidation of Compound (II-1″) in the above-mentionedMethod P.

Compound (XIII) in Method I-2 is prepared, for example, by the followingMethod U.

[Method U]

[wherein the symbols are as defined above.]

This reaction is a method of reacting Compound (III-1) with Compound(XVII) when Q is P(O)(OR⁷)₂ in Compound (XIII), or reacting Compound(III-1) with Compound (XVIII) when Q is PR⁷ ₃ in Compound (XIII), togive Compound (XIII). This reaction is carried out in the same manner asthe preparation of Compound (X) by a reaction of Compound (V′) withCompound (XVII) or Compound (XVIII) in the above-mentioned Method Q.

Moreover, in this process, Compound (III-1) is included in Compound(III), and prepared by the method shown in the above-mentioned Method S.

Compound (IV) in Method E, Compound (IV-1) in Method F, Compound (VII)in Method G, Compound (IX) in Method H, Compound (IV-2) in Method S,and, Compound (IV-3) in Method T (such compounds are all included inCompound (XXII) in Method V of the following formula), are prepared, forexample, by the following Method V.

[Method V]

[wherein Z is a protective group for amino, a protective group forcarboxy, a protective group for hydroxy or a protective group formercapto, —Y″— is —O—, —S—, —N(R³)— or —C(═O)—O— (provided that carbonylcarbon is boned to M²), and the other symbols are as defined above.]

The “protective group” represented by Z includes the protective groupsdescribed below and the like. In this method, the protective group ofCompound (XXIII) is deprotected to give Compound (XXII). The reaction ofdeprotecting the protective group is carried out by a per se knownmethod or a method analogous thereto, for example, according to or byreferring to the conditions described or cited in, for example,“PROTECTIVE GROUPS IN ORGANIC SYNTHESIS”, Second Edition (JOHN WILEY &SONS, INC.) and the like.

Compound (XXIII-1) which is Compound (XXIII) in Method V wherein X² is—O— or —S—, M³ is not a bond is prepared, for example, by the followingMethod W.

[Method W]

[wherein X³ is —O— or —S—, M^(3a) is an optionally substituted divalentaliphatic hydrocarbon group, and the other symbols are as definedabove.]

The “optionally substituted divalent aliphatic hydrocarbon group” inM^(3a) has the same meaning as the above-mentioned “optionallysubstituted divalent aliphatic hydrocarbon group” in the M¹.

[Process 1]

In this method, the hydroxy group of Compound (XXIV) is converted to aleaving group E to give Compound (XXV). This reaction is carried out inthe same manner as the preparation of Compound (V) by converting thehydroxy group of Compound (II-1) to a leaving group E in theabove-mentioned Method L.

[Process 2]

In this method, Compound (XXV) obtained in Process 1 is reacted withCompound (XXVI) to give Compound (XXIII-1). The present method iscarried out, for example, under the same reaction conditions as those ofthe above-mentioned Method D by reacting Compound (II) with Compound(III) to give Compound (I-7).

Compound (XXVI) in [Process 2] of Method W can be prepared by a per seknown method, or is also available as a commercial product.

Compound (XXIII-2) which is Compound (XXIII) in Method V wherein X² is—O— or —S— is prepared, for example, by the following Method X.

[Method X]

[wherein the symbols are as defined above.]

In this method, Compound (XXVII) is reacted with Compound (XXVIII) togive Compound (XXIII-2). The present method for example, is carried outunder the same reaction conditions as those of the above-mentionedMethod D by reacting Compound (II) with Compound (III) to give Compound(I-7).

Moreover, Compound (XXVIII) in the above-mentioned Method X can beprepared by a per se known method, or is also available as a commercialproduct.

Compound (XXIII-3) which is Compound (XXIII) wherein x² is —O— or —S—and M³ is a bond, and used as a starting compound in Method V isprepared, for example, by the following Method Y.

[Method Y]

[wherein the symbols are as defined above.]

In this method, Compound (XXIX) is reacted with Compound (XXX) byso-called Mitsunobu reaction to give Compound (XXIII-3). This reactionis carried out in the same manner as the preparation of Compound (I-8)by reacting Compound (II-1) with Compound (IV-1) in the above-mentionedMethod F.

Moreover, Compound (XXX) in the above-mentioned Method Y can be preparedby a per se known method, or is also available as a commercial product.

Compound (XXIII-4) which is Compound (XXIII) in Method V wherein X² andM⁴ are a bond together, M³ is optionally substituted divalent aliphatichydrocarbon group having 2 or more carbon atoms, or Compound (XXIII-5)is prepared, for example, by the following Method Z.

[Method Z]

[wherein M^(3b) is a bond or an optionally substituted divalentaliphatic hydrocarbon group, R¹³ is a substituent suitably selected froma hydrogen atom, an alkyl group or the substituent which the “divalentaliphatic hydrocarbon group” may have in the above-mentioned M¹, and theother symbols are as defined above.]

The “optionally substituted divalent aliphatic hydrocarbon group” inM^(3b) has the same meaning as the above-mentioned “optionallysubstituted divalent aliphatic hydrocarbon group” in the M¹. The alkylgroup in R¹³ is straight or branched alkyl group, and the number ofcarbon atoms is not particularly limited, preferably less than 18, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl and the like, and the like.

[Process 1] Preparation of Compound (XXIII-4)

Compound (XXIII-4) is obtained by reacting Compound (XXXI)

(1) with phosphonium ylide induced from phosphonium salt (XX-I) (Q=PR⁷₃) to give olefin, which is so-called Wittig reaction, or

(2) with phosphonate carboanion induced from alkylphosphorous diester(XX-I) (Q=P(O) (OR⁷)₂) to give olefin, which is so-calledWittig-Horner-Emmons reaction.

This reaction is carried out in the same manner as the preparation ofCompound (I-12a′) by Wittig reaction or Wittig-Horner-Emmons reaction inthe above-mentioned [Process 1a] of Method I-1.

Compound (XX-I) is can be prepared by a per se known method or a methodanalogous thereto, or is available as a commercial product, or is alsoavailable as a commercial product.

[Process 2] Preparation of Compound (XXIII-5)

This reaction is a method of reducing the double bond of Compound(XXIII-4) obtained in Process 1 to give Compound (XXIII-5). Thisreaction is carried out in the same manner as the preparation ofCompound (I-12a) by hydrogenation of Compound (I-12a′) in [Process 2a]of the above-mentioned Method I.

Compound (XXIII-6) which is Compound (XXIII) in Method V wherein X² andM⁴ are a bond together, R¹ is a hydrogen atom and M³ is an optionallysubstituted divalent aliphatic hydrocarbon group, and Compound (XXIII-7)which is Compound (XXIII) wherein X² and M⁴ are a bond together, M³ isan optionally substituted divalent aliphatic hydrocarbon group and R¹ isnot a hydrogen atom is prepared, for example, by the following MethodAa.

[Method Aa]

[wherein the symbols are as defined above.][Process 1-a]

In this method, Compound (XXV) is reacted with inorganic cyanide to giveCompound (XXXII). This reaction is carried out in the same manner as thepreparation of Compound (XIX) by reacting Compound (V) with inorganiccyanide in [Process 1-a] of the above-mentioned Method Q.

[Process 1-b]

In this method, Compound (XXIV) is reacted with hydrogen cyanide byso-called Mitsunobu reaction to give Compound (XXXII). This reaction iscarried out in the same manner as the preparation of Compound (I-8) byreacting Compound (II-1) with Compound (IV-1) in the above-mentionedMethod F.

Moreover, in the above-mentioned reaction, cyanohydrin (for example,acetonecyanohydrin and the like) may be used as hydrogen cyanide sourceinstead of hydrogen cyanide.

[Process 2]

In this method, Compound (XXXII) obtained in Process 1-a or Process 1-bis hydrolyzed to give Compound (XXIII-6). This reaction is carried outin the same manner as the preparation of Compound (I-1) by hydrolyzingCompound (I-2) in the above-mentioned Method A.

[Process 3]

In this method, Compound (XXIII-6) obtained in Process 2 is esterifiedto give Compound (XXIII-7). This reaction can be carried out by a per seknown method for example, according to or by referring to the conditionsdescribed or cited in, for example, 4th ed. Jikken Kagaku Koza (Maruzen)vol. 22, Organic Synthesis IV, pp. 43-51.

Compound (XXIV) in [Process 1] of Method W, and Compound (XXXI) inMethod Z are known compounds, and can be prepared by a per se knownmethod, or are also available as a commercial product. Furthermore,Compound (XXIV) (Compound (XXIV-1) or Compound (XXIV-2) in the followingMethod Bb) and Compound (XXXI) (Compound (XXXI-1) or Compound (XXXI-2)in the following Method Bb) are prepared, for example, by the followingMethod Bb from Compound (XXIII-8) (the compound combining Compound(XXIII-6) and Compound (XXIII-7) prepared in Method Aa, and Compound(XXIII-4) and Compound (XXIII-5) prepared in Method Z).

[Method Bb]

[wherein R^(13a) is an optionally substituted hydrocarbon group, and theother symbols are as defined above.]

Herein, the above-mentioned “optionally substituted hydrocarbon group”in R^(13a) has the same meaning as the above-mentioned “optionallysubstituted hydrocarbon group” in R¹.

[Process 1]

Compound (XXIV-1) is prepared by reducing Compound (XXIII-8) in Method Junder the same conditions as the preparation of Compound (II-1) byreducing Compound (XIV).

[Process 2]

Compound (XXXI-1) is prepared by oxidizing Compound (XXIV-1) under thesame conditions as the preparation of Compound (XII) by oxidizingCompound (II-1″) in the above-mentioned Method P.

[Process 3]

Compound (XXIV-2) is prepared by reacting Compound (XXXI-1) withR^(13a)-M under the same conditions as the preparation of Compound(II-2) by reacting Compound (XII-1) and R^(8a)-M in the above-mentionedMethod P′.

[Process 4]

Compound (XXXI-2) is prepared by oxidizing Compound (XXIV-2) under thesame conditions as the preparation of Compound (XII) by oxidizingCompound (II-1″) in the above-mentioned Method P.

The compound which is Compound (XIV) in Method J wherein M¹ is a bondand R¹⁰ is an optionally substituted hydrocarbon group, or Compound(XIV′) in Method M wherein M¹ is a bond, can be prepared by a per seknown method. Furan carboxylic acid ester wherein X¹ is an oxygen atomcan be prepared by, for example, the method described or cited in, forexample, 4th ed. Jikken Kagaku Koza (Maruzen) vol. 24, Organic SynthesisVI, pp. 500-504, JP-A-1999-60569, Synthesis 12, p. 1027 (1983) and thelike. Thiophenecarboxylic acid ester wherein X¹ is a sulfur atom can beprepared by, for example, the method described or cited in, for example,4th ed. Jikken Kagaku Koza (Maruzen) vol. 24, Organic Synthesis VI, pp.513-517 and the like.

In the substituent which R, R¹, R², R³, Ring A, M¹, M² or M³ of Compound(I) may have respectively, when the substituent has a convertiblefunctional group (for example, a carboxy group, an amino group, ahydroxy group, a carbonyl group, a mercapto group, ester, cyano group, asulfo group, a halogen atom and the like), the functional group can beconverted by a per se known method or a method analogous thereto to givea variety of compounds.

For example, a carboxy group is convertible by a reaction such asesterification, reduction, amidation, conversion to optionally protectedamino group and the like. An amino group is convertible by a reactionsuch as amidation, sulfonylation, nitrosation, alkylation, arylation,imidation and the like. A hydroxy group is convertible by a reactionsuch as esterification, carbamoylation, sulfonylation, alkylation,arylation, oxidation, halogenation and the like. A carbonyl group isconvertible by a reaction such as reduction, oxidation, imination(containing oximation and hydrazonation), (thio)ketalation,alkylidenation, thiocarbonylation and the like. A mercapto group isconvertible by a reaction such as alkylation, oxidation and the like.Ester or a cyano group is convertible by a reaction such as reduction,hydrolyzation and the like. A sulfo group is convertible by a reactionsuch as sulfonamidation, reduction and the like. A halogen atom isconvertible by various nucleophilic substitution reactions, variouscoupling reactions and the like.

In each of the reactions for synthesizing the above-mentioned objectivecompounds and the starting compounds, a starting compound used having anamino, carboxy, hydroxyl or mercapto as its substituent may be presentas a compound in which a protective group used ordinarily in a peptidechemistry has been introduced into such a substituent, and an objectivecompound can be obtained by deprotection if necessary after thereaction.

A protective group for amino includes, for example, optionallysubstituted C₁₋₆ alkyl-carbonyl (e.g., acetyl, ethylcarbonyl and thelike), phenylcarbonyl, C₁₋₆ alkyloxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl and the like), C₆₋₁₀ aryloxy-carbonyl (e.g.,phenyloxycarbonyl and the like), C₇₋₁₀ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl and the like), formyl, trityl, phthaloyl and the like.Such protective group may be substituted with about 1 to 4 of a halogenatom (e.g., fluorine, chlorine, bromine and iodine and the like), C₁₋₆alkyl-carbonyl (e.g., acetyl, ethylcarbonyl, butylcarbonyl and thelike), nitro and the like.

A protective group for carboxy includes, for example, optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, tert-butyl and the like), phenyl, trityl, silyl and the like.Such protective group may be substituted with about 1 to 4 of a halogenatom (e.g., fluorine, chlorine, bromine and iodine and the like), C₁₋₆alkyl-carbonyl (e.g., acetyl, ethylcarbonyl, butylcarbonyl and thelike), formyl, nitro, and the like.

A protective group for hydroxy includes, for example, optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, tert-butyl and the like), phenyl, C₇₋₁₀ aralkyl (e.g., benzyland the like), C₁₋₆ alkyl-carbonyl (e.g., acetyl, ethylcarbonyl and thelike), C₆₋₁₀ aryloxy-carbonyl (e.g., phenoxycarbonyl and the like),C₇₋₁₀ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl and the like),formyl, pyranyl, furanyl, silyl and the like. Such protective group maybe substituted with 1 to 4 of a halogen atom (e.g., fluorine, chlorine,bromine and iodine and the like), C₁₋₆ alkyl (e.g., methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl and the like), phenyl, C₇₋₁₀aralkyl (e.g., benzyl and the like), nitro and the like. A protectivegroup for mercapto includes, for example, the same as those used as theprotective group for hydroxy.

A deprotection method may be a per se known method or a method analogousthereto such as a treatment with an acid, base, reduction, UV,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate and the like.

Isolation and purification of Compound (I) of the present invention andstarting materials thereof from the reaction mixture, can be carried outby the conventional separation and purification means such asextraction, concentration, filtration, recrystallization, distillation,column chromatography and thin layer chromatography.

When compound (I) thus obtained is obtained as a free form by a reactiondescribed above, it may be converted in accordance with a per se knownmethod or a method analogous thereto (e.g., neutralization, etc.) into asalt, and conversely, when it is obtained as a salt then it may beconverted in accordance with a per se known method or a method analogousthereto into a free form or another salt.

When compound (I) is obtained as an enantiomer, a stereoisomer, apositional isomer or a rotational isomer, these isomers are alsoencompassed in compound (I), and each isomer can be obtained as a singleproduct according to a synthetic method and separation method known perse. For example, when compound (I) has an enantiomer, an enantiomerresolved from this compound is also encompassed in compound (I).

The enantiomer can be produced by a method known per se. To be specific,an optically active synthetic intermediate is used, or the finalracemate product is subjected to optical resolution according to aconventional method to give an enantiomer.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method and the like.

1) Fractional recrystallization method

A salt of a racemate with an optically active compound (e.g.,(+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaricacid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine, etc.) is formed, which is separated by afractional recrystallization method, and a free enantiomer is obtainedby a neutralization step where desired.

2) Chiral Column Method

A racemate or a salt thereof is applied to a column for separation of anenantiomer (chiral column) to allow separation. In the case of a liquidchromatography, for example, a mixture of an enantiomer is applied to achiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) orCHIRAL series (manufactured by Daicel Chemical Industries, Ltd.) and thelike, and developed with water, various buffers (e.g., phosphate buffer)and organic solvents (e.g., ethanol, methanol, isopropanol,acetonitrile, trifluoroacetic acid, diethylamine, etc.) solely or inadmixture to separate the enantiomer. In the case of a gaschromatography, for example, a chiral column such as CP-Chirasil-DeX CB(manufactured by GL Sciences Inc.) and the like is used to allowseparation.

3) Diastereomer Method

A racemic mixture is prepared into a diastereomeric mixture by chemicalreaction with an optically active reagent, which is prepared into asingle substance by a typical separation means (e.g., fractionalrecrystallization, chromatography method, etc.) and the like, andsubjected to a chemical treatment such as hydrolysis and the like toseparate an optically active reagent moiety, whereby an enantiomer isobtained. For example, when compound (I) contains hydroxy or primary orsecondary amino in a molecule, the compound and an optically activeorganic acid (e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylaceticacid], (−)-menthoxyacetic acid, etc.) and the like are subjected tocondensation reaction to give diastereomers of ester form or amide form,respectively. When compound (I) has a carboxylic acid group, thiscompound and an optically active amine or an alcohol reagent aresubjected to condensation reaction to give diastereomers of amide formor ester form, respectively. The separated diastereomer is converted toan enantiomer of the original compound by acid hydrolysis or basehydrolysis.

Compound (I) of the present invention and a pharmacologically acceptablesalt thereof shows excellent preventing and treating action forPPAR-related diseases (e.g., lipid metabolism abnormality and sequelaethereof, diabetes mellitus, hyperlipidemia, arteriosclerotic disease andsequelae thereof (for example, ischemic cardiac disease, cerebraldisease or peripheral arterial occlusion and the like), impaired glucosetolerance and the like), by acting on PPAR. Therefore, it is useful asan agent of controlling PPAR and a prophylactic or therapeutic agent forPPAR-related diseases (e.g., lipid metabolism abnormality and sequelaethereof, diabetes mellitus, hyperlipidemia, arteriosclerotic diseases(for example, ischemic cardiac disease, cerebral disease or peripheralarterial occlusion and the like), impaired glucose tolerance and thelike) in a mammal (e.g., human, monkey, sheep, bovine, horse, dog, cat,rabbit, rat, mouse and the like). Compound (I) of the present inventionis also useful as an agent of raising high-density lipoproteincholesterol, an agent of lowering triglyceride, an agent of lowering alow-density lipoprotein cholesterol, an agent of suppressing progress ofarteriosclerotic plaque and the like. Furthermore, Compound (I) of thepresent invention has regulating action for GPR40 receptor function, andis also useful as an insulin secretion promoter or a prophylactic ortherapeutic agent for diabetes mellitus and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in more detail by the followingExperimental Examples, which are not to be construed as limitative.

When a base, an amino acid and the like are expressed usingabbreviations in the present specification, they are based on theabbreviations of IUPAC-IUB Commission on Biochemical Nomenclature orconventional abbreviations used in the pertinent field, which areexemplified by the following. When an amino acid has an enantiomer, itrefers to an L form, unless specifically indicated.

EXPERIMENTAL EXAMPLE 1 PPARγ-RXRα Heterodimer Ligand Activity

The PPARγ:RXRα:4ERPP/CHO-K1 cells obtained in Reference Example 8a werecultured in Ham's F12 medium [produced by Life Technologies, Inc., USA]containing 10% fetal bovine serum [produced by Life Technologies, Inc.,USA] and inoculated to a 96-well white plate [produced by Corning CosterCorporation, USA] at 2×10⁴ cells/well and cultured overnight at 37° C.in a carbon dioxide gas incubator.

After removal of the medium from the 96-well white plate which had beencultured overnight, Ham's F12 medium containing 80 μl of 0.1% fattyacid-free bovine serum albumin (BSA) and 20 μl of a test compound wereadded, and the plate was incubated at 37° C. in a carbon dioxide gasincubator for 18 to 24 hours. After removal of the medium, 40 μl ofPicaGene 7.5 (produced by Waco Pure Chemicals Industries, Ltd.) dilutedtwofold with HBSS (HANKS' BALANCED SALT SOLUTION) (produced by BIOWHITTAKER) was added, and after stirring, the luciferase activity wasdetermined using 1420 ARVO Multilabel Counter [produced by Wallac].

A fold induction was calculated from the luciferase activity foraddition of each 100 nM of the test compound relative to the luciferaseactivity of the test compound non-administration group as 1. Results areshown in [Table 1].

TABLE 1 Example No. Fold induction 1 (3) 2.8 5 (2) 2.3

As shown above, it was clear that the compound of the present inventionhas excellent PPARγ-RXRα heterodimer ligand activity.

EXPERIMENTAL EXAMPLE 2 PPARδ-RXRα Heterodimer Ligand Activity

At 18 to 24 hours after transfection carried out in Reference Example9a, COS-1 cells were collected, suspended in DMEM medium [manufacturedby Life Technologies, Inc., USA] containing 0.1% fatty acid-free bovineserum albumin (BSA) (produced by Waco Pure Chemicals Industries, Ltd.),and inoculated to each well of a 96-well white plate (produced byCorning, USA) at 1×10⁴ cells/well in 80 μl. Subsequently, 20 μl of atest compound was added, and the plate was incubated under theconditions of 37° C. and 5% CO₂ for 36 to 48 hours. After removal of themedium from the 96-well white plate, 40 μl of PicaGene. LT 7.5 (producedby Waco Pure Chemicals Industries, Ltd.) diluted twofold with HBSS(HANKS' BALANCED SALT SOLUTION) (produced by BIO WHITTAKER) was added,and after stirring, the luciferase activity was determined using 1420ARVO Multilabel Counter [produced by Wallac].

The fold induction was calculated from the luciferase activity foraddition of each 10 nM of the test compound relative to the luciferaseactivity of the test compound non-administration group as 1. Results areshown in [Table 2].

TABLE 2 Example No. Fold induction 5 (9) 6.7 6 (4) 7.4 6 (6) 6.6 6 (24)6.8 6 (26) 5.6

As shown above, it was clear that the compound of the present inventionhas excellent PPARδ-RXRα heterodimer ligand activity.

EXPERIMENTAL EXAMPLE 3 PPARα-RXRα Heterodimer Ligand Activity

At 18 to 24 hours after transfection carried out in Reference Example12a, COS-1 cells were collected, suspended in DMEM medium [manufacturedby Life Technologies, Inc., USA] containing 0.1% BSA (fatty acid-free)(produced by Waco Pure Chemicals Industries, Ltd.), and inoculated toeach well of a 96-well white plate (produced by Corning, USA) at 1×10⁴cells/well in 80 μl. Subsequently, 20 μl of a test compound was added,and the plate was incubated at 37° C. in a carbon dioxide gas incubatorfor 36 to 48 hours. After removal of the medium from the 96-well whiteplate, 40 μl of PicaGene LT 7.5 (produced by Waco Pure ChemicalsIndustries, Ltd.) diluted twofold with HBSS (HANKS' BALANCED SALTSOLUTION) (produced by BIO WHITTAKER) was added, and after stirring, theluciferase activity was determined using 1420 ARVO Multilabel Counter[produced by Wallac].

The fold induction was calculated from the luciferase activity for thewell to which 10 nM of the compound is added, relative to the luciferaseactivity of a control to which the compound is not added as 1. Resultsare shown in [Table 3].

TABLE 3 Example No. Fold induction 1 10.2 2 (1) 10.9 5 (5) 10.1 6 9.3 6(1) 8.9 6 (2) 9.2

As shown above, it was clear that the compound of the present inventionhas excellent PPARα-RXRα heterodimer ligand activity.

EXPERIMENTAL EXAMPLE 4 Receptor Function Regulating Action (AgonistAction) for GPR40

CHO cell strain (No. 104) which have had expressed human GPR40 wasdiluted to contain 3×10⁴ cells/100 μL, and added to a Black walled96-well plate (Costar) at 100 μL/well, and incubated overnight in CO₂incubator. Change of intracellular calcium concentration was measuredwith FLIPR (Molecular Device). The method is as follows. 50 μg ofFluo-3AM (DOJIN) was dissolved in 21 μL of DMSO (DOJIN), and the sameamount of 20% pluronic acid (Molecular Probes) was further addedthereto, and the mixture was mixed. The mixture was added to 10.6 mL ofan assay buffer [prepared by adding 10 mL of solution which was producedby adding 20 mL of 1 M HEPES (pH 7.4) (DOJIN) to 1 L of HBSS(Invitrogen), dissolving 710 mg of probenecid (Sigma) in 5 mL of 1NNaOH, and further adding 5 mL of the above-mentioned HBSS/HEPES solutionthereto and mixing it.] containing 105 μL of fetal bovine serum, to givea fluorescent dye solution. The medium of the cell plate was removed,and immediately, the fluorescent dye solution was added at 100 μL/well,and incubated in CO₂ incubator for 1 hour, allowing the fluorescent dyeto be incorporated into the cells. The cells after incubation werewashed with the above-mentioned assay buffer. The compound to be addedto the cells was diluted with the assay buffer to each concentration,added to the plate for the test sample. After conducting theabove-mentioned pretreatment, intracellular calcium concentration changeafter adding the compound was measured in FLIPR to investigate theagonist action. By dose-response curve with the change of fluorescenceintensity value at 30 seconds after reaction initiation, EC₅₀ value wascalculated.

TABLE 4 Action of regulating receptor function for GPR40 Example No.EC₅₀, μM 5 (8) 0.10 5 (10) 0.87 5 (11) 0.58 6 (4) 0.18 6 (6) 0.16 6 (7)0.29 γ-linolenic acid 2.0

From the results of Table 4, it was clear that the compound of thepresent invention has excellent regulating action for GPR40 receptorfunction.

The genetic engineering procedures described in the following ReferenceExamples 1a to 12a were based on the methods described in the textbook(Maniatis, et al., Molecular Cloning, Cold Spring Harbor Laboratory,1989) or the methods described in the protocols attached to thereagents.

Reference Example 1a Cloning of Human PPARδ Gene

A human PPARδ gene was cloned using a pancreatic cDNA (Toyobo Co., Ltd.,QUICK-Clone cDNA) as a template by means of a PCR method employing aprimer set shown below which was prepared with referring to the basesequence of PPARδ gene reported by Schmidt, A. et al. (Mol. Endocrinol.,vol. 6: 1634-1641 (1992)).

PARD-U; (SEQ ID NO: 1) 5′-AAC GGT ACC TCA GCC ATG GAG CAG CCT CAG GAG G-3′ PARD-L; (SEQ ID NO: 2) 5′-TAA GTC GAC CCG TTA GTA CAT GTC CTT GTA GATC- 3′

The PCR reaction was carried out according to the Hot Start method usingAmpliWax PCR Gem 100 (Takara Shuzo Co., Ltd.). First, 10×LA PCR Buffer(2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primer solution (each 2.5μl) and sterile distilled water (10 μl) were mixed to obtain a bottomlayer solution mixture. Human heart cDNA (1 ng/ml, 1 μl) as a template,10×LA PCR Buffer (3 μl), 2.5 mM dNTP solution (1 μl), TaKaRa LA Taq DNApolymerase (0.5 μl, Takara Shuzo Co., Ltd.) and sterile distilled water(24.5 μl) were mixed to obtain a top layer solution mixture. To theprepared bottom layer solution mixture was added one AmpliWax PCR Gem100 (Takara Shuzo Co., Ltd.), and the mixture was treated at 70° C. for5 minutes and in ice for 5 min, after which the top layer solutionmixture was added to give a reaction mixture of PCR. A tube containingthe reaction mixture was set in a thermal cycler (Perkin Elmer, USA) andtreated at 95° C. for 2 minutes. The cycle of 95° C. for 15 seconds and68° C. for 2 minutes was repeated 45 times and the tube was treated at72° C. for 8 minutes. The obtained PCR product was subjected toelectrophoresis on agarose gel (1%), and a 1.4 kb DNA fragmentcontaining PPARδ gene was recovered from the gel and then inserted intopT7Blue-T vector (Takara Shuzo Co., Ltd.) to give a plasmid pTBT-hPPARδ.

Reference Example 2a Cloning of Human RXRα Gene

A human RXRα gene was cloned using a kidney cDNA (produced by ToyoboCo., Ltd., trademark: QUICK-Clone cDNA) as a template by means of a PCRmethod employing a primer set shown below which was prepared withreferring to the base sequence of RXRα gene reported by Mangelsdorf, D.J. et al. [Nature, vol. 345 (6272), pp. 224-229 (1990)].

XRA-U: (SEQ ID NO: 3) 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3′XRA-L: (SEQ ID NO: 4) 5′-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3′

The PCR reaction was carried out according to the Hot Start method usingAmpliWax PCR Gem 100 (produced by Takara Shuzo Co., Ltd.). First, 10×LAPCR Buffer (2 μl), 2.5 mM DNTP solution (3 μl), 12.5 μM primer solution(each 2.5 μl) and sterile distilled water (10 μl) were mixed to obtain abottom layer solution mixture. Human kidney cDNA (1 ng/ml, 1 μl) as atemplate, 10×LA PCR Buffer (3 μl), 2.5 mM dNTP solution (1 μl), TaKaRaLA Taq DNA polymerase (0.5 μl, produced by Takara Shuzo Co., Ltd.) andsterile distilled water (24.5 μl) were mixed to a top layer solutionmixture.

To the aforementioned bottom layer solution mixture was added oneAmpliWax PCR Gem 100 (produced by Takara Shuzo Co., Ltd.), and themixture was treated at 70° C. for 5 minutes and in ice for 5 minutes,after which the top layer solution mixture was added to give a reactionmixture of PCR. A tube containing the reaction mixture was set in athermal cycler (produced by Perkin Elmer, USA) and treated at 95° C. for2 minutes. The cycle of 95° C. for 15 seconds and 68° C. for 2 minuteswas repeated 35 times and the tube was treated at 72° C. for 8 minutes.

The obtained PCR product was subjected to electrophoresis on agarose gel(1%), and a 1.4 kb DNA fragment containing RXRα gene was recovered fromthe gel and inserted into pT7Blue-T vector (produced by Takara ShuzoCo., Ltd.) to give a plasmid pTBT-hRXRα.

Reference Example 3a Preparation of Plasmids for Expressing Human PPARδand RXRα

A 5.6 kb KpnI-SalI fragment of plasmid pMCMVneo and a 1.3 kb KpnI-SalIfragment containing hPPARδ gene of plasmid pTBT-hPPARδ described inReference Example 1a were ligated to give plasmid pMCMVneo-hPPARδ.

Reference Example 4a Preparation of Plasmids for Expressing Human PPARδand RXRα

A 5.6 kb EcoRI-SalI fragment of plasmid pMCMVneo and a 1.4 kb EcoRI-XhoIfragment containing hRXRα gene of plasmid pTBT-hRXRα described inReference Example 2a were ligated to give plasmid pMCMVneo-hRXRα.

Reference Example 5a Preparation of Reporter Plasmids

A DNA fragment containing a PPAR-responding element (PPRE) of an acylCoA oxidase was prepared using the following 5′-terminal phosphorylatedsynthetic DNA.

PPRE-U: (SEQ ID NO: 5) 5′-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3′PPRE-L: (SEQ ID NO: 6) 5′-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3′

First, PPRE-U and PPRE-L were annealed and inserted into a SalI site ofplasmid pBlueScript SK. By determining the base sequence of the insertedfragment, based on which plasmid pBSS-PPRE4, plasmid pBSS-PPRE4 in which4 PPREs were ligated in tandem was selected.

A HSV thymidine kinase minimum promoter (TK promoter) region was clonedusing pRL-TK vector (produced by Promega, USA) as a template by means ofa PCR method employing a primer set shown below which was prepared withreferring to the base sequence of the promoter region of thymidinekinase gene reported by Luckow, B. et al. [Nucleic Acids Res., Vol. 15(13), p. 5490 (1987)].

TK-U: 5′-CCCAGATCTCCCCAGCGTCTTGTCATTG-3′ (SEQ ID NO: 7) TK-L:5′-TCACCATGGTCAAGCTTTTAAGCGGGTC-3′ (SEQ ID NO: 8)

The PCR reaction was carried out according to the Hot Start method usingAmpliWax PCR Gem 100 (Takara Shuzo Co., Ltd.). First, 10×LA PCR Buffer(2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primer solution (each 2.5μl) and sterile distilled water (10 μl) were mixed to obtain a bottomlayer solution mixture. pRL-TK vector (produced by Promega, USA, 1 μl)as a template, 10×LA PCR Buffer (3 μl), 2.5 mM DNTP solution (1 μl),TaKaRa LA Taq DNA polymerase (0.5 μl, produced by Takara Shuzo Co.,Ltd.) and sterile distilled water (24.5 μl) were mixed to obtain a toplayer solution-mixture.

To the prepared bottom layer solution mixture was added one AmpliWax PCRGem 100 (produced by Takara Shuzo Co., Ltd.), and the mixture wastreated at 70° C. for 5 minutes and in ice for 5 minutes, after whichthe top layer solution mixture was added to give a reaction mixture ofPCR. A tube containing the reaction mixture was set in a thermal cycler(produced by Perkin Elmer, USA) and treated at 95° C. for 2 minutes. Thecycle of 95° C. for 15 seconds and 68° C. for 2 minutes was repeated 35times and the tube was treated at 72° C. for 8 minutes.

The obtained PCR product was subjected to electrophoresis on agarose gel(1%), and a 140 b DNA fragment containing TK promoter was recovered fromthe gel and inserted into pT7 Blue-T vector (produced by Takara ShuzoCo., Ltd.). A fragment containing the TK promoter, which was obtained bycleaving this plasmid with restriction enzymes BglII and NcoI, wasligated with a BglII-NcoI fragment of plasmid pGL3-Basic vector[produced by Promega, USA] to give a plasmid pGL3-TK.

The NheI-XhoI fragment (4.9 kb) of the obtained plasmid pGL3-TK and theNheI-XhoI fragment (200 bp) of plasmid pBSS-PPRE4 were ligated to give aplasmid pGL3-4ERPP-TK. This plasmid pGL3-4ERPP-TK was cleaved with BamHI(produced by Takara Shuzo Co., Ltd.) and then treated with T4 DNApolymerase (produced by Takara Shuzo Co., Ltd.) to form a blunt terminalwhereby obtaining a 1.6 kb of a DNA fragment. Both DNA fragments wereligated to construct a reporter plasmid pGL3-4ERPP-TK neo.

Subsequently, a reporter plasmid in which the direction of aPPAR-responding element (PPRE) of the reporter plasmid pGL3-4ERPP-TK neois reversed was obtained. That is, a 4.9 kb KpnI-NheI fragment ofplasmid pGL3-TK and a 200 bp KpnI-XbaI fragment of plasmid pBSS-PPRE4were ligated to obtain a plasmid pGL3-PPRE4-TK. This plasmidpGL3-PPRE4-TK was cleaved with BamHI (produced by Takara Shuzo Co.,Ltd.) and then treated with T4 DNA polymerase (produced by Takara ShuzoCo., Ltd.) to form a blunt terminal. On the other hand, pGFP-C1(produced by Toyobo Co., Ltd.) was cleaved with Bsu36I (NEB) and thentreated with T4 DNA polymerase (produced by Takara Shuzo Co., Ltd.) toform a blunt terminal whereby obtaining a 1.6 kb of a DNA fragment. BothDNA fragments were ligated to construct a reporter plasmid pGL3-4ERPP-TKneo.

Reference Example 6a Cloning of Human PPARγ Gene

A human PPARγ gene was cloned using heart cDNA (produced by Toyobo Co.,Ltd., trademark: QUICK-Clone cDNA) as a template by means of a PCRmethod empolying a primer set shown below which was prepared withreferring to the base sequence of PPARγ gene reported by Greene et al.[Gene Expr., vol. 4 (4-5), pp. 281-299 (1995)].

PAG-U: (SEQ ID NO: 9) 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3′PAG-L: (SEQ ID NO: 10) 5′-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3′

The PCR reaction was carried out according to the Hot Start method usingAmpliWax PCR Gem 100 (produced by Takara Shuzo Co., Ltd.). First, 10×LAPCR Buffer (2 μl), 2.5 mM dNTP solution (3 μl), 12.5 μM primer solution(each 2.5 μl) and sterile distilled water (10 μl) were mixed to obtain abottom layer solution mixture. Human heart cDNA (1 ng/ml, 1 μl) as atemplate, 10×LA PCR Buffer (3 μl), 2.5 mM dNTP solution (1 μl), TaKaRaLA Taq DNA polymerase (0.5 μl, produced by Takara Shuzo Co., Ltd.) andsterile distilled water (24.5 μl) were mixed to obtain a top layersolution mixture.

To the prepared bottom layer solution mixture was added one AmpliWax PCRGem 100 (produced by Takara Shuzo Co., Ltd.), and the mixture wastreated at 70° C. for 5 minutes and in ice for 5 minutes, after whichthe top layer solution mixture was added to give a reaction mixture ofPCR. A tube containing the reaction mixture was set in a thermal cycler(produced by Perkin Elmer, USA) and treated at 95° C. for 2 minutes. Thecycle of 95° C. for 15 sec and 68° C. for 2 minutes was repeated 35times and the tube was treated at 72° C. for 8 minutes.

The obtained PCR product was subjected to electrophoresis on agarose gel(1%), and a 1.4 kb DNA fragment containing PPARγ gene was recovered fromthe gel and inserted into pT7Blue-T vector (produced by Takara ShuzoCo., Ltd.) to give a plasmid pTBT-hPPARγ.

Reference Example 7a Preparation of Plasmids for Expressing Human PPARγand RXRα

A 7.8 kb FspI-NotI fragment of plasmid pVgRXR (produced by Invitrogen,USA) and a 0.9 kb FspI-NotI fragment containing the RXRα gene of theplasmid pTBT-hRXRα obtained in Reference Example 2a were ligated to givea plasmid pVgRXR2. The pVgRXR2 was cleaved with BstXI and then treatedwith T4 DNA polymerase (produced by Takara Shuzo Co., Ltd.) to form ablunt terminal. Then, cleavage with KpnI gave a 6.5 kb DNA fragment.

On the other hand, the plasmid pTBT-hPPARγ obtained in Reference Example6a was cleaved with SalI and then treated with T4 DNA polymerase(produced by Takara Shuzo Co., Ltd.) to form a blunt terminal. Then,cleavage with KpnI gave a 1.4 kb DNA fragment containing human PPARγgene.

Both DNA fragments were ligated to construct plasmid pVgRXR2-hPPARγ.

Reference Example 8a Introduction of Plasmids for Expressing Human PPARγand RXRα and Reporter Plasmid into CHO-K1 Cell and Establishment ofExpressed Cell

A CHO-K1 cell was grown in a cell culture flask of 150 cm² (produced byCorning Coaster Corporation, USA) using Ham's F12 Medium (produced byLife Technologies, Inc.) containing 10% fetal bovine serum (produced byLife Technologies, Inc., USA), and scraped by treating with 0.5 g/Ltripsin-0.2 g/L EDTA (ethylenediaminetetraacetic acid, produced by LifeTechnologies, Inc., USA). The cell was washed with PBS(phosphate-buffered saline) (produced by Life Technologies, Inc., USA),centrifuged (1000 rpm, 5 minutes) and suspended in PBS. Using a genepulser (produced by Bio-Rad Laboratories, USA), DNA was introduced intothe cell under the following conditions.

Namely, 8×10⁶ cells, 10 μg of plasmid pVgRXR2-hPPARγ obtained inReference Example 7a and 10 μg of reporter plasmid pGL3-4ERPP-TK neoobtained in Reference Example 5a were placed in a cuvette having a 0.4cm gap and subjected to electroporation at 0.25 kV voltage and 960 μFcapacitance. Thereafter, the cell was placed in the 10% fetal bovineserum-containing Ham's F12 Medium, cultured for 24 hours, scraped againand centrifuged, and then suspended in Ham's F12 Medium containing 10%fetal bovine serum supplemented with geneticin (500 μg/ml, produced byLife Technologies, Inc. USA) and zeocin (250 μg/ml, produced byInvitrogen, USA), diluted to 10⁴ cell/ml, inoculated to a 96 well plate(produced by Corning Costar Corporation, USA) and cultured in a carbondioxide gas incubator at 37° C. to give a geneticin-and zeocin-resistanttransformant.

The obtained transformant strain was cultured in a 24-well plate(produced by Corning Costar Corporation, USA). 10 μM pibglitazonehydrochloride was added thereto and a strain in which the luciferase wasexpressed and induced, i.e., PPARγ:RXRα:4ERPP/CHO-K1, was selected.

Reference Example 9a Introduction of Plasmids for Expressing Human PPARδand RXRα and Reporter Plasmid into COS-1 Cell

A COS-1 cell was inoculated in a cell culture flask (produced byCorning, USA) of 150 cm² at 5×10⁶ cells/50 ml, and the plate wasincubated under the conditions of 37° C. and 5% CO₂ for 24 hours.Transfection was carried out with lipofectamine (produced by Invitrogen,USA). A transfection mixture solution was prepared by mixing 125 μl oflipofectamine, 100 μl of PLUS Reagent, 2.5 μg of pMCMVneo-hPPARδ(obtained in Reference Example 3a), 2.5 μg of pMCMVneo-hRXRα (obtainedin Reference Example 4a), 5 μg of reporter plasmid pGL3-4ERPP-TK neo(obtained in Reference Example 5a) and 5 μg of pRL-tk [produced byPromega, USA] with 5 ml of opti-MEM (produced by Invitrogen, USA). Tothe COS-1 cell washed with opti-MEM, the above-mentioned transfectionmixture solution and 20 ml of opti-MEM were added, and then incubatedunder the conditions of 37° C. and 5% CO₂ for 3 hours. Then, 25 ml ofDMEM medium [manufactured by Life Technologies, Inc., USA] containing0.1% fatty acid-free bovine serum albumin (BSA) (produced by Waco PureChemicals Industries, Ltd.) was added thereto, and then incubated underthe conditions of 37° C. and 5% CO₂ for 18 to 24 hours.

Reference Example 10a Cloning of Human PPARα Gene

A human PPARα gene was cloned using hepatic cDNA (Toyobo Co., Ltd.,QUICK-Clone cDNA) as a template by means of a PCR method employing aprimer set shown below which was prepared with referring to the basesequence of PPARα gene reported by Sher, T. et al. (Biochemistry, vol.32, pp5598-5604 (1993)).

PAA-U: (SEQ ID NO: 11) 5′-AAA GGA TCC CGC GAT GGT GGA CAC AGA AAG CCC-3′PAA-L: (SEQ ID NO: 12) 5′-CCC GTC GAC TCA GTA CAT GTC CCT GTA GAT CTC-3′

The PCR reaction was carried out according to the Hot Start method usingAmpliWax PCR Gem 100 (produced by Takara Shuzo Co., Ltd.). As a bottomlayer solution mixture, 10×native pfu Buffer (2 μl), 2.5 mM dNTPsolution (3 μl), 12.5 μM primer solution (each 2.5 μl) and steriledistilled water (10 μl) were mixed. As a top layer solution mixture,human hepatic cDNA (1 ng/ml, 1 μl) as a template, 10× native pfu Buffer(3 μl), 2.5 mM dNTP solution (1 μl), native pfu DNA polymerase (0.5 μl,produced by STRATAGENE, USA) and sterile distilled water (24.5 μl) weremixed. To the prepared bottom layer solution mixture was added oneAmpliWax PCR Gem 100 (produced by Takara Shuzo Co., Ltd.), and themixture was treated at 70° C. for 5 minutes and in ice for 5 minutes,after which the top layer solution mixture was added to give a reactionmixture of PCR. A tube containing the reaction mixture was set in athermal cycler (produced by Perkin Elmer, USA) and treated at 95° C. for2 minutes. The cycle of 95° C. for 15 seconds and 68° C. for 2 minuteswas repeated 45 times and the tube was treated at 72° C. for 8 minutes.

The obtained PCR product was subjected to electrophoresis on agarose gel(1%), and a 1.4 kb DNA fragment containing PPARα gene was recovered fromthe gel and inserted into pT7Blue Blunt vector (produced by Takara ShuzoCo., Ltd.) to give a plasmid pTBB-hPPARα.

Reference Example 11a Preparation of Plasmids for Expressing Human PPARα

A 5.6 kb KpnI-SalI fragment of plasmid pMCMVneo and a 1.4 kb KpnI-SalIfragment containing human PPARα gene of plasmid pTBB-hPPARα described inReference Example 10a were ligated to give plasmid pMCMVneo-hPPARα.

Reference Example 12a Co-Introduction of Plasmids for Expressing HumanPPARα and RXRα and Reporter Plasmid into COS-1 Cell

A COS-1 cell was inoculated in a cell culture flask (produced byCorning, USA) of 150 cm² at 5×10⁶ cells/50 ml, and incubated under theconditions of 37° C. and 5% CO₂ for 24 hours. Transfection was carriedout with lipofectamine (produced by Invitrogen, USA). A transfectionmixture solution was prepared by mixing 125 μl of lipofectamine, 100 μlof PLUS Reagent, 2.5 μg of pMCMVneo-hPPARα (obtained in ReferenceExample 11a), 2.5 μg of pMCMVneo-hRXRα (obtained in Reference Example4a), 5 μg of reporter plasmid pGL3-4ERPP-TK neo (obtained in ReferenceExample 5a) and 5 μg of pRL-tk [produced by Promega, USA] with 5 ml ofopti-MEM (produced by Invitrogen, USA). To COS-1 cell washed withopti-MEM, the above-mentioned transfection mixture solution and 20 ml ofopti-MEM were added, and then incubated under the conditions of 37° C.and 5% CO₂ for 3 hours. Then, 25 ml of DMEM medium [manufactured by LifeTechnologies, Inc., USA] containing 0.1% fatty acid-free bovine serumalbumin (BSA) (produced by Waco Pure Chemicals Industries, Ltd.) wasadded thereto, and then incubated under the conditions of 37° C. and 5%CO₂ for 18 to 24 hours.

The present invention is hereinafter described in more detail by meansof the following Examples and Reference Examples which are not to beconstrued as limitative. Also, these Examples may be modified withoutdeparting from the scope of the present invention.

¹H-NMR spectra were recorded on a Varian Gemini-200 (200 MHz) or MERCURY300 (300 MHz) spectrometer using tetramethylsilane as an internalstandard and chemical shifts are given in δ values (ppm). In the mixtureof solvents, the value indicated means the mixing ratio of volume ofeach solvent, unless otherwise stated. Unless otherwise stated, %indicates % by weight. Unless otherwise stated, an elution solvent insilica gel column chromatography is indicated as a capacity ratio. Theterm “room temperature” in the present specification usually means atemperature from about 20 to about 30° C.

Further, each symbol used in Examples and Reference Examples indicatesthe following meanings. s: singlet, d: doublet, t: triplet, q: quartet,br: broad, dd: double doublet, dt: double triplet, td: triple doublet,dq: double quartet, tt: triple triplet, ddd: double double doublet, m:multiplet, Hz: hertz, CDCl₃: deuterated chloroform, DMSO-d₆: deuterateddimethylsulfoxide, CD₃OD: deuterated methanol, and %: % by weight

Reference Example 1 1-Fluoro-4-(2-nitro-1-propenyl)benzene

A mixture of 4-fluorobenzaldehyde (17.0 g), acetic acid (11.5 g),methylamine-hydrochloride (3.70 g), sodium acetate (4.50 g) andnitromethane (41.2 g) was stirred at 100° C. for 1.5 hours. The reactionsolution was diluted with water, and then 3 times extracted with ethylacetate. The collected organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained crude product was crystallized from diethyl ether—hexane toobtain an objective product (18.4 g) as crystals.

Melting point 59-61° C. ¹H-NMR (CDCl₃) δ 2.45 (3H, s), 7.16 (2H, d),7.44 (2H, dd), 8.06 (1H, s).

Reference Example 2 Methyl 4-(4-fluorophenyl)-2,5-dimethyl-3-furoate

To a solution of 1-fluoro-4-(2-nitro-1-propenyl)benzene (2.49 g) inmethanol (20 ml) was added piperidine (1.36 ml) and methyl acetoacetate(1.60 g) at room temperature, and the mixture was stirred as suchovernight. After the reaction solution was concentrated under reducedpressure, water (10 ml) and concentrated hydrochloric acid (3 ml) wereadded thereto, and the mixture was stirred at room temperature for 1hour. The reaction solution was twice extracted with ethyl acetate andthe collected organic layer was dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (ethylacetate:hexane=1:9) to obtain an objective product (1.59 g) as a solidmatter. The obtained matter was recrystallized from cold methanol toobtain crystals. Melting point 34-35° C.; ¹H-NMR (CDCl₃) δ 2.18 (3H, s),2.56 (3H, s), 3.66 (3H, s), 7.05 (2H, t), 7.21 (2H, dd).

Reference Example 2(1) to Reference Example 2(3)

In the same manner as in Reference Example 2, the below-describedcompounds were obtained from the β-ketoester form corresponding to1-fluoro-4-(2-nitro-1-propenyl) benzene.

Reference Example 2(1) Ethyl2-cyclohexyl-4-(4-fluorophenyl)-5-methyl-3-furoate

Melting point 71-72° C.; ¹H-NMR (CDCl₃) □δ 1.09 (3H, t), 1.24-1.93 (10H,m), 2.17 (3H, s), 3.78 (1H, tt), 4.10 (2H, q), 7.04 (2H, t), 7.21 (2H,dd).

Reference Example 2(2) Ethyl4-(4-fluorophenyl)-2-isopropyl-5-methyl-3-furoate

Melting point 27-28° C.; ¹H-NMR (CDCl₃) δ 1.09 (3H, t), 1.30 (6H, d),2.18 (3H, s), 3.65-3.79 (1H, m), 4.11 (2H, q), 7.04 (2H, t), 7.21 (2H,dd).

Reference Example 2(3) Ethyl4-(4-fluorophenyl)-5-methyl-2-phenyl-3-furoate

Melting point 78-79° C.; ¹H-NMR (CDCl₃) δ 1.02 (3H, t), 2.30 (3H, s),4.10 (2H, q), 7.09 (2H, t), 7.19-7.48 (5H, m), 7.82 (2H, dd).

Reference Example 3 Methyl 5-(4-fluorophenyl)-2-methyl-3-furoate

To a solution of 1,8-azabicyclo[5.4.0]-7-undecene (44.5 g) in toluene(100 ml) was added dropwise a solution of methyl acetoacetate (33.9 g)in toluene (50 ml) with ice-cooling. After the reaction solution wasstirred as such for 10 minutes, a solution of2-chloro-4′-fluoroacetophenone (50.4 g) in toluene (100 ml) was addeddropwise with ice-cooling and the mixture was further stirred at roomtemperature for 2 hours. The resulting precipitate was filtered andwashed with toluene. The obtained toluene solution was passed throughsilica gel, and the silica gel was washed with ethyl acetate-hexane(1:1). The collected solution was concentrated under reduced pressure,ethyl acetate-hexane was removed to obtain a toluene solution. To thetoluene solution was added 4-toluenesulfonic acid•1 hydrate (5.55 g) andthe mixture was stirred at 100° C. for 2 hours. The reaction solutionwas washed with an aqueous sodium hydrogen carbonate solution and theaqueous layer was extracted with ethyl acetate. The organic layer wascollected and dried over magnesium sulfate. The solvent was distilledoff under reduced pressure. The obtained crude product was crystallizedfrom cold methanol to obtain an objective product (37.6 g) as crystals.

Melting point 96-97° C.; ¹H-NMR (CDCl₃) δ 2.64 (3H, s), 3.85 (3H, s),6.81 (1H, s), 7.08 (2H, t), 7.60 (2H, dd).

Reference Example 3(1) to Reference Example 3(9)

In the same manner as in Reference Example 3, the below-describedcompounds obtained from the β-ketoester form corresponding to thephenacyl halide.

Reference Example 3(1) Methyl2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate

Melting point 91-92° C.; ¹H-NMR (CDCl₃) δ 2.67 (3H, s), 3.87 (3H, s),7.00 (1H, s), 7.63 (2H, d), 7.73 (2H, d).

Reference Example 3(2) Methyl2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furoate

Melting point 81-82° C.; ¹H-NMR (CDCl₃) δ 1.33 (3H, t), 3.09 (2H, q),3.86 (3H, s), 6.99 (1H, s), 7.62 (2H, d), 7.72 (2H, d).

Reference Example 3(3) Methyl2-isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furoate

Melting point 61-62° C.; ¹H-NMR (CDCl₃) □ 1.35 (6H, d), 3.77-3.87 (1H,m), 3.85 (3H, s), 6.98 (1H, s), 7.62 (2H, d), 7.72 (2H, d).

Reference Example 3(4) 15 Methyl2-butyl-5-[4-(trifluoromethyl)phenyl]-3-furoate

Melting point 172-174° C.; ¹H-NMR (CDCl₃) δ 0.98 (3H, t), 1.38-1.50 (2H,m), 1.71-1.82 (2H, m), 3.11 (2H, t), 7.04 (1H, s), 7.64 (2H, d), 7.74(2H, d).

Reference Example 3(5) Methyl2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furoate

Melting point 66-67° C.; ¹H-NMR (CDCl₃) δ 2.65 (3H, s), 3.85 (3H, s),6.87 (1H, s), 7.23 (2H, d), 7.64 (2H, d).

Reference Example 3(6) Methyl 5-(3-methoxyphenyl)-2-methyl-3-furoate

Melting point 67-68° C.; ¹H-NMR (CDCl₃) δ 2.65 (3H, s), 3.85 (6H, s),6.83 (1H, ddd), 6.88 (1H, s), 7.16-7.34 (3H, m).

Reference Example 3(7) Methyl2-methyl-5-[3-(trifluoromethyl)phenyl]-3-furoate

Melting point 74-75° C.; ¹H-NMR (CDCl₃) δ 2.67 (3H, s), 3.86 (3H, s),6.97 (1H, s), 7.49-7.51 (2H, m), 7.77-7.80 (1H, m), 7.87 (1H, s).

Reference Example 3(8) Methyl 2-ethyl-5-(3-methoxyphenyl)-3-furoate

An oily matter; ¹H-NMR (CDCl₃) δ 1.32 (3H, t), 3.07 (2H, q), 3.85 (3H,s), 3.85 (3H, s), 6.82 (1H, ddd), 6.86 (1H, s), 7.16-7.32 (3H, m).

Reference Example 3(9) Methyl 5-(4-chlorophenyl)-2-methyl-3-furoate

Melting point 105-106° C.; ¹H-NMR (CDCl₃) δ 2.64 (3H, s), 3.85 (3H, s),6.87 (1H, s), 7.35 (2H, d), 7.56 (2H, d).

Reference Example 4 Ethyl 5-phenyl-2-(trifluoromethyl)-3-furoate

To a suspension of suspended matter (5.51 g) of 60% sodium hydride inliquid paraffin in 1,2-dimethoxyethane (100 ml) was added dropwise asolution of ethyl 4,4,4-trifluoroacetoacetate (23.1 g) in1,2-dimethoxyethane (50 ml) at room temperature. The reaction solutionwas stirred for 0.5 hour, and then to the reaction solution was addeddropwise 2-bromoacetophenone (24.9 g) at room temperature. The mixturewas further stirred at 80° C. overnight. The reaction solution waspoured into water and twice extracted with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The obtained oily matter was dissolved in toluene (200 ml) and4-toluenesulfonic acid.1 hydrate (4.77 g) was added thereto. Thereaction mixture was heated under reflux for 8 hours under dehydrationcondition by using the reaction vessel equipped with a Dean-Stark trap.The reaction solution was washed with an aqueous sodium hydrogencarbonate solution and the aqueous layer was extracted with ethylacetate. The collected organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane to hexane:ethyl acetate=15:1) and crystallized from coldmethanol to obtain an objective product (10.7 g) as crystals. Meltingpoint 44-45° C.; ¹H-NMR (CDCl₃) δ 1.39 (3H, t), 4.38 (2H, q), 7.05 (1H,s), 7.38-7.49 (3H, m), 7.68-7.74 (2H, m).

Reference Example 5 5-(4-Fluorophenyl)-2-methyl-3-furoic acid

A mixture of methyl 5-(4-fluorophenyl)-2-methyl-3-furoate (15.36 g),sodium hydroxide (5.25 g), methanol (100 ml), water (50 ml) andtetrahydrofuran (50 ml) was stirred at room temperature overnight. Thereaction solution was concentrated, diluted with water and acidifiedwith dilute hydrochloric acid. Then, the reaction solution was twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was distilled off under reducedpressure. The obtained crude product was crystallized from diethylether-hexane to obtain an objective product (13.4 g) as crystals.Melting point 217-218° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.65 (3H, s), 6.83(1H, s), 7.07 (2H, t), 7.60 (2H, dd).

Reference Example 5(1) to Reference Example 5(6)

In the same manner as in Reference Example 5, the below-describedcompounds were obtained from the 3-furancarboxylate derivative obtainedin Reference Example 3(1) to Reference Example 3(5) and ReferenceExample 4.

Reference Example 5(1) 2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furoicacid

Melting point 199-200° C.; ¹H-NMR (CDCl₃) δ 2.67 (3H, s), 7.02 (1H, s),7.61 (2H, d), 7.72 (2H, d).

Reference Example 5(2) 2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furoicacid

Melting point 186-187° C.; ¹H-NMR (CDCl₃) δ 1.36 (3H, t) 3.14 (2H, q),7.05 (1H, s), 7.65 (2H, d), 7.75 (2H, d).

Reference Example 5(3)2-Isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furoic acid

Melting point 187-188° C.; ¹H-NMR (CDCl₃) δ 1.38 (6H, d) 3.80-3.94 (1H,m), 7.04 (1H, s), 7.65 (2H, d), 7.75 (2H, d).

Reference Example 5(4) 2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furoicacid

Melting point 172-174° C.; ¹H-NMR (CDCl₃) δ 0.98 (3H, t) 1.38-1.50 (2H,m), 1.71-1.82 (2H, m), 3.11 (2H, t), 7.04 (1H, s), 7.64 (2H, d), 7.74(2H, d).

Reference Example 5(5) 2-Methyl-5-[4-(trifluoromethoxy)phenyl]-3-furoicacid

Melting point 145-146° C.; ¹H-NMR (CDCl₃) δ 2.70 (3H, s), 6.93 (1H, s),7.24 (2H, d), 7.67 (2H, d).

Reference Example 5(6) 5-Phenyl-2-(trifluoromethyl)-3-furoic acid

Melting point 171-173° C.; ¹H-NMR (CDCl₃) δ 7.09 (1H, s), 7.37-7.48 (3H,m), 7.72 (2H, d).

Reference Example 6 [5-(4-Fluorophenyl)-2-methyl-3-furyl]methanol

To a suspension of aluminum lithium hydride (3.67 g) in tetrahydrofuran(200 ml) was added dropwise a solution of methyl5-(4-fluorophenyl)-2-methyl-3-furoate (15.1 g) in tetrahydrofuran (50ml) with ice-cooling and the mixture was stirred at 0° C. for 1 hour.The reaction solution was ice-cooled, and water (3.5 ml), a 15% aqueoussodium hydroxide solution (3.5 ml) and water (8 ml) were sequentiallyadded dropwise. Excess aluminum lithium hydride was decomposed and thenthe resulting mixture was stirred as such at room temperature for 2hours. The produced precipitate was filtered off and then washed withethyl acetate. The solvent of the collected filtrate was distilled offunder reduced pressure. The obtained crude product was crystallized fromhexane to obtain an objective product (11.9 g) as crystals. Meltingpoint 80-82° C.; ¹H-NMR (CDCl₃) δ 1.61 (1H, br s), 2.35 (3H, s), 4.50(2H, s), 6.56 (1H, s), 7.05 (2H, t), 7.58 (2H, dd).

Reference Example 6(1) to Reference Example 6(14)

In the same manner as in Reference Example 6, the below-describedcompounds were obtained from the 3-furancarboxylate derivative obtainedin Reference Example 2, Reference Example 2(1) to Reference Example2(3), Reference Example 3(1) to Reference Example 3(9) and ReferenceExample 4.

Reference Example 6(1)[4-(4-Fluorophenyl)-2,5-dimethylfuran-3-yl]methanol

Paraffinoid solid; ¹H-NMR (CDCl₃) δ 2.26 (3H, s), 2.33 (3H, s), 4.41(2H, s), 7.10 (2H, t), 7.36 (2H, dd).

Reference Example 6(2)[4-(4-Fluorophenyl)-2-isopropyl-5-methylfuran-3-yl]methanol

Melting point 72-73° C.; ¹H-NMR (CDCl₃) δ 1.31 (6H, d), 2.27 (3H, s),3.02-3.23 (1H, m), 4.41 (2H, s), 7.09 (2H, t), 7.36 (2H, dd).

Reference Example 6(3)[2-Cyclohexyl-4-(4-fluorophenyl)-5-methylfuran-3-yl]methanol

Melting point 137-138° C.; ¹H-NMR (CDCl₃) δ 1.22-1.94 (10H, m), 2.26(3H, s), 2.75 (1H, tt), 4.41 (2H, s), 7.09 (2H, t), 7.36 (2H, dd).

Reference Example 6(4)[4-(4-Fluorophenyl)-5-methyl-2-phenylfuran-3-yl]methanol

Melting point 153-154° C.; ¹H-NMR (CDCl₃) δ 2.37 (3H, s) 4.57 (2H, s),7.14 (2H, t), 7.29-7.49 (5H, m), 7.76 (2H, d).

Reference Example 6(5){2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

Melting point 90-91° C.; ¹H-NMR (CDCl₃) δ 2.37 (3H, s), 4.52 (2H, s),6.74 (1H, s), 7.59 (2H, d), 7.68 (2H, d)

Reference Example 6(6){2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

Melting point 52-53° C.; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 1.41 (1H, br s),2.74 (2H, q), 4.53 (2H, s), 6.75 (1H, s), 7.59 (2H, d), 7.70 (2H, d).

Reference Example 6(7){2-Isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

Melting point 100-101° C.; ¹H-NMR (CDCl₃) δ 1.33 (6H, d), 1.39 (1H, brs), 3.10-3.19 (1H, m), 4.54 (2H, s), 6.74 (1H, s), 7.59 (2H, d), 7.69(2H, d).

Reference Example 6(8){2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

Melting point 74-75° C.; ¹H-NMR (CDCl₃) δ 0.95 (3H, t), 1.33-1.45 (3H,m), 1.63-1.73 (2H, m), 2.71 (2H, t), 4.52 (2H, s), 6.76 (1H, s), 7.59(2H, d) 7.69 (2H, d)

Reference Example 6(9){2-Methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methanol

Melting point 53-55° C.; ¹H-NMR (CDCl₃) δ 1.41 (1H, br t) 2.37 (3H, s),4.52 (2H, d), 6.64 (1H, s), 7.20 (2H, d), 7.63 (2H, d)

Reference Example 6(10) [5-Phenyl-2-(trifluoromethyl)-3-furyl]methanol

Melting point 57-58° C.; ¹H-NMR (CDCl₃) δ 1.71 (1H, t), 4.73 (2H, d),6.82 (1H, s), 7.32-7.44 (3H, m), 7.69 (2H, d).

Reference Example 6(11) [5-(3-Methoxyphenyl)-2-methyl-3-furyl]methanol

Melting point 61-62° C.; ¹H-NMR (CDCl₃) δ 1.43 (1H, t), 2.37 (3H, s),3.85 (3H, s), 4.51 (2H, d), 6.64 (1H, s), 6.79 (1H, ddd), 7.15-7.32 (3H,m).

Reference Example 6(12){2-Methyl-5-[3-(trifluoromethyl)phenyl]-3-furyl}methanol

Melting point 39-41° C.; ¹H-NMR (CDCl₃) δ 1.43 (1H, t), 2.38 (3H, s),4.53 (2H, d), 6.73 (1H, s), 7.46 (2H, d), 7.77 (1H, t), 7.86 (1H, s).

Reference Example 6(13) [2-Ethyl-5-(3-methoxyphenyl)-3-furyl]methanol

Melting point 66-67° C.; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 1.38 (1H, t),2.73 (2H, q), 3.85 (3H, s), 4.52 (2H, d), 6.63 (1H, s), 6.79 (1H, ddd),7.17-7.32 (3H, m).

Reference Example 6(14) [5-(4-Chlorophenyl)-2-methyl-3-furyl]methanol

Melting point 129-130° C.; ¹H-NMR (CDCl₃) δ 2.35 (3H, s) 4.50 (2H, s),6.62 (1H, s), 7.31 (2H, d), 7.53 (2H, d).

Reference Example 7 2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde

{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (4.77 g) andactive manganese dioxide (25 g) were stirred at room temperature inhexane (50 ml) and diethyl ether (10 ml) overnight. Insolubles werefiltered and washed with ethyl acetate. The solvent of the collectedfiltrate was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=6:1) to obtain an objective product (3.21 g) as a solid matter.The obtained matter was recrystallized from hexane to obtain crystals.

Melting point 95-96° C.; ¹H-NMR (CDCl₃) δ 1.42 (3H, t), 3.07 (2H, q),7.03 (1H, s), 7.65 (2H, d), 7.75 (2H, d), 9.98 (1H, s).

Reference Example 7(1) to Reference Example 7(3)

In the same manner as in Reference Example 7, the below-describedcompounds were obtained from the 3-furylmethanol derivative obtained inReference Example 6(5), Reference Example 6(8) and Reference Example 6.

Reference Example 7(1)2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde

Melting point 106-107° C.; ¹H-NMR (CDCl₃) δ 2.69 (3H, s), 7.02 (1H, s),7.63 (2H, d), 7.74 (2H, d), 9.96 (1H, s).

Reference Example 7(2)2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde

An oily matter; ¹H-NMR (CDCl₃) δ 0.98 (3H, t), 1.38-1.51 (2H, m),1.75-1.85 (2H, m), 3.04 (2H, t), 7.03 (1H, s), 7.65 (2H, d), 7.75 (2H,d), 9.97 (1H, s).

Reference Example 7(3) 5-(4-Fluorophenyl)-2-methyl-3-furaldehyde

Melting point 60-61° C.; ¹H-NMR (CDCl₃) δ 2.66 (3H, s), 6.84 (1H, s),7.09 (2H, t), 7.62 (2H, dd), 9.96 (1H, s).

Reference Example 8 Ethyl(2E)-3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acrylate

To a solution of ethyl diethylphosphonoacetate (3.02 g) in toluene (30ml) was added a suspended matter (0.54 g) of 60% sodium hydride inliquid paraffin with ice-cooling and the mixture was stirred for 0.5hour. A solution of 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde(3.01 g) in toluene (30 ml) was added thereto and the mixture wasstirred at room temperature overnight. The reaction solution was pouredinto water and twice extracted with diethyl ether. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1to 9:1) to obtain an objective product (3.48 g) as a solid matter.

Melting point 82-83° C.; ¹H-NMR (CDCl₃) δ 1.33 (3H, t), 1.34 (3H, t),2.85 (2H, q), 4.26 (2H, q), 6.14 (1H, d), 6.85 (1H, s), 7.57 (1H, d),7.62 (2H, d), 7.73 (2H, d).

Reference Example 8(1) and Reference Example 8(2)

In the same manner as in Reference Example 8, the below-describedcompounds were obtained from the 3-furaldehyde derivative obtained inReference Example 7(1) and Reference Example 7(2).

Reference Example 8(1) Ethyl(2E)-3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acrylate

Melting point 78-79° C.; ¹H-NMR (CDCl₃) δ 1.33 (3H, t), 2.48 (3H, s),4.26 (2H, q), 6.14 (1H, d), 6.84 (1H, s), 7.55 (1H, d), 7.62 (2H, d),7.73 (2H, d).

Reference Example 8(2) Ethyl(2E)-3-{2-butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acrylate

An oily matter; ¹H-NMR (CDCl₃) δ 0.96 (3H, t), 1.28-1.50 (2H, m), 1.34(3H, t), 1.64-1.79 (2H, m), 2.82 (2H, t), 4.26 (2H, q), 6.15 (1H, d),6.86 (1H, s), 7.57 (1H, d), 7.63 (2H, d), 7.74 (2H, d).

Reference Example 9 Ethyl3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionate

A solution of ethyl(2E)-3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acrylate (3.30 g)in toluene (30 ml) and ethanol (5 ml) was hydrogenated usingchlorotris(triphenylphosphine) rhodium (I) (0.45 g) as a catalyst atroom temperature under normal pressure overnight. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=9:1) to obtain an objective product (3.31 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.25 (3H, t), 1.27 (3H, t), 2.50-2.76 (6H, m), 4.14(2H, q), 6.59 (1H, s), 7.58 (2H, d), 7.68 (2H, d).

Reference Example 9(1) and Reference Example 9(2)

In the same manner as in Reference Example 9, the below-describedcompounds were obtained from the ethyl acrylate derivative obtained inReference Example 8(1) and Reference Example 8 (2).

Reference Example 9(1) Ethyl3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionate

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.31 (3H, s), 2.53 (2H, t), 2.69 (2H, t),4.13 (2H, q), 6.57 (1H, s), 7.56 (2H, d), 7.65 (2H, d)

Reference Example 9(2) Ethyl3-{2-butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionate

An oily matter; ¹H-NMR (CDCl₃) δ 0.95 (3H, t), 1.25 (3H, t) 1.32-1.45(2H, m), 1.60-1.70 (2H, m), 2.54 (2H, t), 2.65 (2H, t), 2.71 (2H, t),4.14 (2H, q), 6.58 (1H, s), 7.57 (2H, d), 7.66 (2H, d).

Reference Example 103-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid

To a solution of ethyl3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionate (0.540 g) inmethanol (3 ml) and tetrahydrofuran (5 ml) was added a 1 N aqueoussodium hydroxide solution (3.2 ml) and the mixture was stirred at roomtemperature overnight. The reaction solution was concentrated anddiluted with water. After the reaction solution was acidified withdilute hydrochloric acid, the resultant was twice extracted with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure. Theobtained crude product was crystallized from hexane to obtain anobjective product (0.413 g) as crystals. Melting point 94-95° C.; ¹H-NMR(CDCl₃) δ 1.26 (3H, t), 2.59-2.75 (6H, m), 6.59 (1H, s), 7.57 (2H, d),7.67 (2H, d).

Reference Example 10(1) and Reference Example 10(2)

In the same manner as in Reference Example 10, the below-describedcompounds were obtained from the ethyl propionate derivative obtained inReference Example 9(1) and Reference Example 9(2).

Reference Example 10(1)3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid

Melting point 112-113° C.; ¹H-NMR (CDCl₃) δ 2.31 (3H, s) 2.58-2.63 (2H,m), 2.69-2.74 (2H, m), 6.58 (1H, s), 7.57 (2H, d), 7.66 (2H, d).

Reference Example 10(2)3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid

Melting point 79-80° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t), 1.32-1.44 (2H,m), 1.60-1.70 (2H, m), 2.59-2.75 (6H, m), 6.59 (1H, s), 7.57 (2H, d),7.67 (2H, d).

Reference Example 113-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-ol

To a suspension of aluminum lithium hydride (0.46 g) in tetrahydrofuran(50 ml) was added dropwise a solution of ethyl3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionate (2.76 g) intetrahydrofuran (30 ml) with ice-cooling and the mixture was stirred atroom temperature for 1 hour. The reaction solution was ice-cooled, andthen water (0.5 ml), a 15% aqueous sodium hydroxide solution (0.5 ml)and water (1.5 ml) were sequentially added dropwise thereto. Excessaluminum lithium hydride was decomposed and then the resulting mixturewas stirred as such at room temperature for 2 hours. The producedprecipitate was filtered off and then washed with ethyl acetate. Thesolvent of the collected filtrate was distilled off under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=6:1 to 3:1) to obtain an objectiveproduct (1.64 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.31 (1H, br s), 1.76-1.89 (2H, m), 2.48(2H, t), 2.67 (2H, q), 3.70 (2H, t), 6.60 (1H, s), 7.58 (2H, d), 7.69(2H, d).

Reference Example 11(1) and Reference Example 11(2)

In the same manner as in Reference Example 11, the below-describedcompounds were obtained from the ethyl propionate derivative obtained inReference Example 9(1) and Reference Example 9(2).

Reference Example 11(1)3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-ol

An oily matter; ¹H-NMR (CDCl₃) δ 1.77-1.86 (2H, m), 2.30 (3H, s), 2.47(2H, t), 3.68 (2H, t), 6.57 (1H, s), 7.57 (2H, d), 7.67 (2H, d).

Reference Example 11(2)3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-ol

An oily matter; ¹H-NMR (CDCl₃) δ 0.95 (3H, t), 1.27 (1H, br s),1.32-1.45 (2H, m), 1.61-1.71 (2H, m), 1.78-1.87 (2H, m), 2.48 (2H, t),2.64 (2H, t), 3.69 (2H, br t), 6.59 (1H, s), 7.57 (2H, d), 7.67 (2H, d).

Reference Example 12{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acetic acid

1) To a solution of{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (1.48 g) intetrahydrofuran (100 ml) was added acetone cyanohydrin (0.80 ml) andtributylphosphine (2.89 ml), and then finally1,1′-(azodicarbonyl)dipiperidine (2.92 g) was added. The mixture wasstirred at room temperature for 3 days. Hexane and toluene were addedthereto, the solid matter was filtered and washed with toluene. Thefiltrate was concentrated under reduced pressure, and then the residuewas purified by silica gel column chromatography (hexane:ethylacetate=10:1 to 5:1) to obtain{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acetonitrile (1.76 g) asan oily matter.

¹H-NMR (CDCl₃) δ 2.37 (3H, s), 3.50 (2H, s), 6.70 (1H, s), 7.61 (2H, d),7.70 (2H, d).

2) To a solution of{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acetonitrile (1.76 g) inethanol (10 ml) was added 8 N sodium hydroxide (10 ml) and the mixturewas heated under reflux overnight. After completing the reaction, thereaction mixture was acidified with concentrated hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and then purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to obtain an objective product (0.68 g) ascrystals.

Melting point 123-125° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 3.45 (2H, s),6.70 (1H, s), 7.58 (2H, d), 7.68 (2H, d).

Reference Example 12(1) [5-(4-Fluorophenyl)-2-methyl-3-furyl]acetic acid

In the same manner as in Reference Example 12, an objective product wasobtained from [5-(4-fluorophenyl)-2-methyl-3-furyl]methanol obtained inReference Example 6.

Melting point 107-108° C.; ¹H-NMR (CDCl₃) δ 2.31 (3H, s), 3.43 (2H, s),6.50 (1H, s), 7.03 (2H, t), 7.56 (2H, dd).

Reference Example 132-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethanol

A suspension of aluminum lithium hydride (0.10 g) in tetrahydrofuran (5ml) was ice-cooled and{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acetic acid (0.43 g) intetrahydrofuran (5 ml) was added dropwise thereto. The mixture wasstirred with ice-cooling for 30 minutes and then at room temperature for1 hour. After completing the reaction, water (0.1 ml), 15% sodiumhydroxide (0.1 ml) and water (0.3 ml) were sequentially added and themixture was stirred at room temperature for 30 minutes. The precipitatedcrystals were filtered and washed with tetrahydrofuran. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) toobtain an objective product (0.28 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.33 (3H, s), 2.64 (2H, t), 3.81 (2H, t), 6.63 (1H, s),7.58 (2H, d), 7.68 (2H, d).

Reference Example 13(1) 2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]ethanol

In the same manner as in Reference Example 13, an objective product wasobtained from [5-(4-fluorophenyl)-2-methyl-3-furyl]acetic acid obtainedin Reference Example 12(1).

Melting point 52-53° C.; ¹H-NMR (CDCl₃) δ 1.46 (1H, br s) 2.31 (3H, s),2.63 (2H, t), 3.79 (2H, br q), 6.44 (1H, s), 7.04 (2H, t), 7.57 (2H,dd).

Reference Example 14 1-[5-(4-Fluorophenyl)-2-methyl-3-furyl]ethanol

To a solution of 5-(4-fluorophenyl)-2-methyl-3-furaldehyde (2.54 g) intetrahydrofuran (40 ml) was added dropwise a 1 N solution of methylmagnesium bromide (18.7 ml) in tetrahydrofuran at −78° C. and thereaction solution was stirred at room temperature overnight. Thereaction solution was poured into an aqueous ammonium chloride solutionand twice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane-hexane:ethyl acetate=3:1) andcrystallized from hexane to obtain an objective product (2.43 g) aspowders.

Melting point 50-52° C.; ¹H-NMR (CDCl₃) δ 1.48 (3H, d), 1.60 (1H, d),2.35 (3H, s), 4.85 (1H, dq), 6.57 (1H, s), 7.04 (2H, t), 7.57 (2H, dd).

Reference Example 14(1)1-[5-(4-Fluorophenyl)-2-methyl-3-furyl]butan-1-ol

In the same manner as in Reference Example 14, an objective product wasobtained using 5-(4-fluorophenyl)-2-methyl-3-furaldehyde andpropylmagnesium bromide.

Melting point 73-74° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t), 1.26-1.47 (2H,m), 1.59 (1H, d), 1.62-1.72 (1H, m), 1.77-1.87 (1H, m), 2.34 (3H, s),4.62 (1H, dt), 6.54 (1H, s), 7.04 (2H, t), 7.57 (2H, dd).

Reference Example 15 Ethyl3-{[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzoate

To a solution of 5-(4-fluorophenyl)-2-methyl-3-furoic acid (4.47 g) andN,N-dimethylformamide (2 drops) in tetrahydrofuran (50 ml) was addeddropwise oxalyl chloride (3.54 ml) at room temperature and the mixturewas stirred for 0.5 hour. The solvent of the reaction solution wasdistilled off under reduced pressure to obtain a crude product of acidchloride as a solid matter. Ethyl 3-aminobenzoate (3.69 g) and sodiumhydrogen carbonate (3.41 g) were stirred in tetrahydrofuran (50 ml), andthe obtained solid matter was dissolved in tetrahydrofuran (50 ml). Thereactant was added dropwise at room temperature and the mixture wasstirred as such overnight. The reaction solution was diluted with ethylacetate, washed with water and dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theobtained residue was crystallized from diethyl ether-hexane to obtain anobjective product (7.39 g) as crystals.

Melting point 171-172° C.; ¹H-NMR (CDCl₃) δ 1.40 (3H, t), 2.70 (3H, s),4.38 (2H, q), 6.72 (1H, s), 7.10 (2H, t), 7.44 (1H, t), 7.59-7.66 (3H,m), 7.81 (1H, td), 8.02-8.06 (2H, m).

Reference Example 15(1) Ethyl3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzoate

In the same manner as in Reference Example 15, an objective product wasobtained from 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoic acid inReference Example 5(1).

Melting point 161-162° C.; ¹H-NMR (CDCl₃) δ 1.39 (3H, t) 2.73 (3H, s),4.38 (2H, q), 6.92 (1H, s), 7.40-7.48 (1H, m), 7.64-7.72 (3H, m),7.77-7.84 (3H, m), 8.02-8.07 (2H, m).

Reference Example 16 Ethyl3-{N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]-N-methylamino}benzoate

Ethyl 3-{N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzoate (1.07 g)was dissolved in N,N-dimethylformamide (5 ml) and tetrahydrofuran (5ml), and a suspended matter (0.13 g) of 60% sodium hydride in liquidparaffin was added at room temperature. The mixture was stirred as suchfor 0.5 hour. To the mixture was added methyl iodide (0.36 ml) at roomtemperature and the mixture was stirred as such overnight. The reactionsolution was poured into water and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=6:1 to 2:1) to obtain an objective product (1.18 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.39 (3H, t), 2.47 (3H, s), 3.47 (3H, s), 4.38 (2H, q),5.69 (1H, s), 6.98 (2H, t), 7.26-7.44 (4H, m), 7.89-7.97 (2H, m).

Reference Example 16(1) to 16 (3)

In the same manner as in Reference Example 16, ethyl3-{N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzoate was alkylatedwith the corresponding alkyl halide to obtain the below-describedcompounds.

Reference Example 16(1) Ethyl3-{N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]-N-propylamino}benzoate

Melting point 119-120° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t) 1.39 (3H, t),1.55-1.70 (2H, m), 2.47 (3H, s), 3.86 (2H, t), 4.38 (2H, q), 5.63 (1H,s), 6.97 (2H, t), 7.27-7.34 (3H, m), 7.40 (1H, t), 7.87 (1H, t), 7.95(1H, td).

Reference Example 16(2) Ethyl3-{N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]-N-heptylamino}benzoate

An oily matter; ¹H-NMR (CDCl₃) δ 0.86 (3H, t), 1.22-1.35 (8H, m), 1.39(3H, t), 1.53-1.66 (2H, m), 2.47 (3H, s), 3.87 (2H, t), 4.38 (2H, q),5.63 (1H, s), 6.97 (2H, t), 7.27-7.34 (3H, m), 7.40 (1H, t), 7.87 (1H,t), 7.95 (1H, td).

Reference Example 16(3) Ethyl3-{N-benzyl-N-[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzoate

An oily matter; ¹H-NMR (CDCl₃) δ 1.36 (3H, t), 2.52 (3H, s), 4.34 (2H,q), 5.11 (2H, s), 5.63 (1H, s), 6.97 (2H, t), 7.10-7.16 (1H, m),7.23-7.37 (8H, m), 7.81 (1H, t), 7.90 (1H, td).

Reference Example 175-(4-(Fluorophenyl)-N-[3-(hydroxymethyl)phenyl]-2-methyl-3-furamide

While ethyl 3-{[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzoate(1.01 g) and sodium borohydride (0.52 g) were stirred in tetrahydrofuran(30 ml), methanol (3 ml) was added at room temperature, and then themixture was heated under reflux for 2 hours. After the reaction solutionwas cooled to room temperature, an aqueous ammonium chloride solutionwas added and the mixture was stirred as such for 1 hour. The mixturewas twice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The obtained residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:1 to 1:2), andcrystallized from diisopropyl ether-hexane to obtain an objectiveproduct (0.72 g) as crystals.

Melting point 163-164° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.70 (3H, s), 3.51(1H, t), 4.68 (2H, d), 7.01-7.14 (4H, m), 7.32 (1H, t), 7.60-7.69 (4H,m), 8.56 (1H, br s).

Reference Examples 17(1) to 17(5)

In the same manner as in Reference Example 17, the ester forms obtainedin Reference Example 16, Reference Example 16(1) to Reference Example16(3) and Reference Example 15(1) were reduced to obtain thebelow-described compounds.

Reference Example 17(1)5-(4-Fluorophenyl)-N-[3-(hydroxymethyl)phenyl]-N,2-dimethyl-3-furamide

An oily matter; ¹H-NMR (CDCl₃) δ 1.76 (1H, t), 2.49 (3H, s) 3.45 (3H,s), 4.69 (2H, d), 5.64 (1H, s), 6.97 (2H, t), 7.09 (1H, td), 7.21 (1H,s), 7.24-7.38 (4H, m).

Reference Example 17(2)5-(4-Fluorophenyl)-N-[3-(hydroxymethyl)phenyl]-2-methyl-N-propyl-3-furamide

Melting point 116-117° C.; ¹H-NMR (CDCl₃) δ 0.93 (3H, t), 1.56-1.77 (3H,m), 2.49 (3H, s), 3.82 (2H, t), 4.69 (2H, d), 5.58 (1H, s), 6.97 (2H,t), 7.08 (1H, td), 7.18 (1H, s), 7.26-7.38 (4H, m).

Reference Example 17(3)5-(4-Fluorophenyl)-N-heptyl-N-[3-(hydroxymethyl)phenyl]-2-methyl-3-furamide

Melting point 89-91° C.; ¹H-NMR (CDCl₃) δ 0.86 (3H, t), 1.21-1.33 (10H,m), 1.55-1.70 (3H, m), 2.49 (3H, s), 3.85 (2H, t), 4.69 (2H, d), 5.58(1H, s), 6.97 (2H, t), 7.07 (1H, d), 7.18 (1H, s), 7.26-7.38 (4H, m).

Reference Example 17(4)N-benzyl-5-(4-fluorophenyl)-N-[3-(hydroxymethyl)phenyl]-2-methyl-3-furamide

An oily matter; ¹H-NMR (CDCl₃) δ 1.65 (1H, t), 2.53 (3H, s) 4.61 (2H,d), 5.08 (2H, s), 5.59 (1H, s), 6.92-7.02 (3H, m), 7.06 (1H, s),7.23-7.34 (9H, m).

Reference Example 17(5)N-[3-(hydroxymethyl)phenyl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furamide

Melting point 173-174° C.; ¹H-NMR (CDCl₃) δ 2.72 (3H, s) 4.71 (2H, d),6.89 (1H, s), 7.14 (1H, d), 7.31-7.39 (1H, m), 7.50 (2H, d), 7.62-7.66(3H, m), 7.75 (2H, d).

Reference Example 18N-(3-formylphenyl)-2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furamide

To a solution ofN-[3-(hydroxymethyl)phenyl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furamide(0.98 g) in tetrahydrofuran (10 ml) was added manganese dioxide (3.0 g)and the mixture was stirred at room temperature for 2 hours. Manganesedioxide (1.0 g) was further added thereto and the mixture was stirredfor 1 hour. Insolubles were filtered and then concentrated under reducedpressure. The residue was purified by recrystallization (hexane-ethylacetate) to obtain an objective product (0.76 g) as crystals. Meltingpoint 183-184° C.; ¹H-NMR (CDCl₃) δ 2.75 (3H, s), 6.93 (1H, s),7.50-7.68 (5H, m), 7.77 (2H, d), 7.98 (1H, d), 8.11 (1H, s), 10.02 (1H,s).

Reference Example 19 tert-Butyl 3-(hydroxymethyl)phenylcarbamate

3-Aminobenzylalcohol (10.9 g), triethylamine (24.6 ml) and di-tert-butyldicarbonate (21.2 g) were heated under reflux in tetrahydrofuran (100ml) for 3 hours. The reaction solution was cooled to room temperatureand then the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1 to 3:1) to obtain an objective product (15.0g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.51 (9H, s), 1.96 (1H, br t), 4.65 (2H, d), 6.55 (1H,br s), 7.01-7.05 (1H, m), 7.18-7.31 (2H, m), 7.43 (1H, s).

Reference Example 20 Ethyl({3-[(tert-butoxycarbonyl)amino)benzyl}thio)acetate

To a solution of tert-butyl 3-(hydroxymethyl)phenylcarbamate (4.94 g)and triethylamine (4.63 ml) in ethyl acetate (50 ml) was added dropwisea solution of methanesulfonyl chloride (3.04 g) in ethyl acetate (20 ml)with ice-cooling, and then the mixture was stirred as such for 0.5 hour.The produced precipitate was filtered and washed with ethyl acetate. Thesolvent of the obtained filtrate was distilled off under reducedpressure to obtain a crude product of methanesulfonic ester as an oilymatter. The obtained oily matter was dissolved in tetrahydrofuran (30ml). To the mixture was added at room temperature a solution obtained bystirring ethyl thioglycollate (2.93 g) and1,8-diazabicyclo[5.4.0]-7-undecene (3.71 ml) in tetrahydrofuran (30 ml)for 0.5 hour. The mixture was stirred as such overnight. The reactionsolution was diluted with ethyl acetate, washed with an aqueous sodiumhydrogen carbonate solution twice, and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane ethyl acetate=15:1 to 6:1) to obtain an objective product (6.75g) as a solid matter.

Melting point 75-76° C.; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 1.51 (9H, s),3.07 (2H, s), 3.79 (2H, s), 4.18 (2H, q), 6.47 (1H, br s), 6.97-7.03(1H, m), 7.23-7.30 (2H, m), 7.36 (1H, s).

Reference Example 21 Ethyl [(3-aminobenzyl)thio]acetate.hydrochloride

To a solution of ethyl({3-[(tert-butoxycarbonyl)amino]benzyl}thio)acetate (6.57 g) in ethanol(30 ml) was added a 4 N solution (30 ml) of hydrogen chloride in ethylacetate at room temperature and the mixture was stirred at 60° C. for0.5 hour. The solvent of the mixture was distilled off under reducedpressure. The obtained residue was crystallized from diethyl ether toobtain an objective product (4.94 g) as crystals. Melting point 112-114°C.; ¹H-NMR (CD₃OD) δ 1.27 (3H, t), 3.13 (2H, s), 3.90 (2H, s), 4.14 (2H,q), 7.28-7.34 (1H, m), 7.42-7.52 (3H, m).

Reference Example 22 3-(Methoxymethoxy)benzaldehyde

To a solution of 3-hydroxybenzaldehyde (13.0 g) in tetrahydrofuran (150ml) was added a suspended matter (4.68 g) of 60% sodium hydride inliquid paraffin with ice-cooling and the mixture was stirred for 15minutes. Chloromethylmethyl ether (10.3 g) was added thereto withice-cooling, and the mixture was stirred at room temperature overnight.The reaction solution was poured into water and twice extracted withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=15:1 to 9:1) to obtain an objectiveproduct (16.4 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.49 (3H, s), 5.23 (2H, s), 7.27-7.31 (1H, m), 7.45(1H, t), 7.50-7.54 (2H, m), 9.97 (1H, s).

Reference Example 23 3-(Methoxymethoxy)benzyl alcohol

To a solution of 3-(methoxymethoxy)benzaldehyde (16.4 g) in methanol(100 ml) was slowly added sodium borohydride (3.74 g) and the mixturewas stirred with ice-cooling at room temperature overnight. The reactionsolution was concentrated under reduced pressure, poured into water andthen extracted with ethyl acetate twice. The collected organic layer wasdried over anhydrous magnesium sulfate and passed through silica gel.Then, the solvent was distilled off under reduced pressure to obtain anobjective product (15.7 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.75 (1H, br s), 3.48 (3H, s), 4.67 (2H, s), 5.18 (2H,s), 6.94-7.06 (3H, m), 7.28 (1H, t).

Reference Example 24 Ethyl {[3-(methoxymethoxy)benzyl]thio}acetate

To a solution of 3-(methoxymethoxy)benzylalcohol (15.7 g) andtriethylamine (19.5 ml) in ethyl acetate (150 ml) was added dropwise asolution of methanesulfonyl chloride (12.8 g) in ethyl acetate (50 ml)with ice-cooling and the mixture was stirred as such for 0.5 hour. Theproduced precipitate was filtered and washed with ethyl acetate. Thesolvent of the obtained filtrate was distilled off under reducedpressure to obtain a crude product of methanesulfonic ester as an oilymatter. The obtained oily matter was dissolved in tetrahydrofuran (50ml). To the mixture was added at room temperature a solution obtained bystirring ethyl thioglycollate (12.3 g) and1,8-diazabicyclo[5.4.0]-7-undecene (15.3 ml) in tetrahydrofuran (30 ml)for 0.5 hour. The mixture was stirred as such overnight. The reactionsolution was diluted with ethyl acetate and washed with an aqueoussodium hydrogen carbonate solution twice. The reaction solution wasdried over anhydrous magnesium sulfate and passed through silica gel.Then, the solvent was distilled off under reduced pressure to obtain anobjective product (25.3 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.09 (2H, s), 3.48 (3H, s) 3.80 (2H, s),4.19 (2H, q), 5.18 (2H, s), 6.91-7.02 (3H, m), 7.24 (1H, t).

Reference Example 25 Ethyl [(3-hydroxybenzyl)thio]acetate

To a solution of ethyl {[3-(methoxymethoxy)thio]acetate (14.5 g) inethanol (100 ml) was added concentrated hydrochloric acid (10 ml) atroom temperature and the mixture stirred as such for 1 day. The solventof the mixture was distilled off under reduced pressure to obtain acrude product which was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to obtain an objective product (12.3 g) as anoily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.08 (2H, s), 3.78 (2H, s), 4.18 (2H, q),5.12 (1H, br s), 6.74 (1H, dd), 6.84 (1H, s), 6.89 (1H, d), 7.19 (1H, t)

Reference Example 26 S-{3-[(Benzyloxy)methoxy]benzyl}thioacetate

To a solution of 3-hydroxybenzylalcohol (23.8 g) in tetrahydrofuran (100ml) was added 1,8-diazabicyclo[5.4.0]-7-undecene (29.2 g) withice-cooling and the mixture was stirred for 0.5 hour. A solution ofbenzylchloromethyl ether (30.0 g) in tetrahydrofuran (50 ml) was addedwith ice-cooling and the mixture was stirred at room temperatureovernight. The reaction solution was poured into dilute hydrochloricacid and twice extracted with ethyl acetate. The collected organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain an oily matter.

To a solution of the obtained oily matter and triethylamine (32.0 ml) inethyl acetate (150 ml) was added dropwise a solution of methanesulfonylchloride (24.1 g) in ethyl acetate (50 ml) with ice-cooling and themixture was stirred as such for 0.5 hour. The produced precipitate wasfiltered and washed with ethyl acetate. The solvent of the obtainedfiltrate was distilled off under reduce pressure to obtain a crudeproduct of methanesulfonic ester as an oily matter. The obtained oilymatter was dissolved in N,N-dimethylformamide (100 ml) and potassiumthioacetate (26.3 g) was added thereto at room temperature and themixture was stirred as such overnight. The reaction solution was pouredinto water and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1)to obtain an objective product (25.8 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.34 (3H, s), 4.10 (2H, s), 4.71 (2H, s), 5.28 (2H, s),6.92-7.01 (3H, m), 7.22 (1H, t), 7.33 (5H, s).

Reference Example 27 Ethyl2-({3-[(benzyloxy)methoxy]benzyl}thio)-2-methylpropionate

To a solution of S-{3-[(benzyloxy)methoxy]benzyl}thioacetate (6.46 g) inmethanol (30 ml) was added at room temperature those obtained dissolvingsodium hydroxide (0.85 g) in methanol (20 ml) and water (2 ml), and themixture was stirred as such for 1 hour. The solvent of the mixture wasdistilled off under reduce pressure to obtain a solid matter. Theobtained solid matter was dissolved in N,N-dimethylformamide (25 ml) andethyl 2-bromo-2-methylpropionate (5.00 g) was added thereto at roomtemperature, and the mixture was stirred at 60° C. overnight. Thereaction solution was poured into water and twice extracted with ethylacetate. The collected organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=15:1) to obtain an objective product (7.67 g) asan oily matter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.54 (6H, s), 3.82 (2H, s), 4.13 (2H, q),4.71 (2H, s), 5.28 (2H, s), 6.94-7.05 (3H, m), 7.21 (1H, t), 7.33 (5H,s).

Reference Example 28 Ethyl 2-[(3-hydroxybenzyl)thio]-2-methylpropionate

To a solution ethyl2-({3-[(benzyloxy)methoxy]benzyl}thio)-2-methylpropionate (7.67 g) inethanol (50 ml) was added concentrated hydrochloric acid (5 ml) at roomtemperature and the mixture was stirred at 60° C. for 2 hours. Thesolvent of the mixture was distilled off under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=6:1) to obtain an objective product (3.81 g) as anoily matter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.53 (6H, s), 3.78 (2H, s), 4.11 (2H, q),4.96 (1H, s), 6.69 (1H, dd), 6.79 (1H, t), 6.86 (1H, d), 7.14 (1H, t).

Reference Example 29 Ethyl {[3-(methoxymethoxy)benzyl]oxy}acetate

To a solution of 3-(methoxymethoxy)benzylalcohol (4.53 g) in1,2-dimethoxyethane (150 ml) was added a suspended matter (1.29 g) of60% sodium hydride in liquid paraffin with ice-cooling and the mixturewas stirred for 0.5 hour. Ethyl bromoacetate (6.75 g) was added theretowith ice-cooling and the mixture was stirred at room temperatureovernight. The reaction solution was poured into water and twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=15:1 to 6:1) to obtain anobjective product (4.62 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.48 (3H, s), 4.10 (2H, s), 4.23 (2H, q),4.61 (2H, s), 5.18 (2H, s), 6.96-7.05 (3H, m), 7.27 (1H, t).

Reference Example 30 Ethyl [(3-(hydroxybenzyl)oxy]acetate

To a solution of ethyl {[3-(methoxymethoxy)benzyl]oxy}acetate (4.62 g)in ethanol (50 ml) was added concentrated hydrochloric acid (3 ml) atroom temperature and the mixture was stirred at room temperatureovernight. The solvent of the mixture was distilled off under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to obtain an objective product(2.36 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 4.10 (2H, s), 4.24 (2H, q) 4.59 (2H, s),5.18 (1H, s), 6.75-6.81 (1H, m), 6.88-6.92 (2H, m), 7.22 (1H, t).

Reference Example 31 Methoxymethyl[3-(methoxymethoxy)phenyl]acetate

To a solution of (3-hydroxyphenyl)acetic acid (10.5 g) intetrahydrofuran (150 ml) was added N-ethyldiisopropylamine (26.3 ml)with ice-cooling and the mixture was stirred for 0.5 hour.Chloromethylmethyl ether (13.8 g) was added with ice-cooling and themixture was stirred at 60° C. overnight. The reaction solution waspoured into water and twice extracted with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=6:1 to 3:1) to obtain an objective product (14.8 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 3.42 (3H, s), 3.47 (3H, s), 3.64 (2H, s), 5.17 (2H, s),5.24 (2H, s), 6.92-6.98 (3H, m), 7.24 (1H, t).

Reference Example 32 [3-(Methoxymethoxy)phenyl]acetic acid

A mixture of methoxymethyl [3-(methoxymethoxy)phenyl]acetate (14.8 g),sodium hydroxide (4.93 g), methanol (50 ml), water (100 ml) andtetrahydrofuran (50 ml) was stirred at room temperature overnight. Thereaction solution was concentrated and diluted with water. The reactionsolution was acidified with dilute hydrochloric acid, and then extractedwith ethyl acetate twice. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was distilled off under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain an objectiveproduct (11.2 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.48 (3H, s), 3.63 (2H, s), 5.17 (2H, s), 6.91-6.99(−3H, m), 7.26 (1H, t).

Reference Example 33 Ethyl 4-[3-(methoxymethoxy)phenyl]-3-oxobutanoate

To a solution [3-(methoxymethoxy)phenyl]acetic acid (11.2 g) intetrahydrofuran (150 ml) was added 1,1′-carbonyldiimidazole (10.2 g) atroom temperature and the mixture was stirred as such for 3 hours. To themixture was added a monopotassium salt of monoethyl malonate (10.7 g)and magnesium chloride (3.00 g) at room temperature and the mixture wasstirred at 60° C. overnight. The reaction solution was diluted withethyl acetate and water, and acidified with concentrated hydrochloricacid. Then, the ethyl acetate layer was separated and the aqueous layerwas extracted with ethyl acetate. The collected organic layer was driedover anhydrous sodium sulfate and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate 6:1 to 3:1) to obtain anobjective product (10.7 g) as liquid.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 3.45 (2H, s), 3.47 (3H, s), 3.80 (2H, s),4.17 (2H, q), 5.16 (2H, s), 6.83-6.98 (3H, m), 7.25 (1H, t).

Reference Example 34 Ethyl 4-[3-(methoxymethoxy)phenyl]butanoate

To a solution of ethyl 4-[3-(methoxymethoxy)phenyl]-3-oxobutanoate (6.28g) in ethanol (40 ml) was slowly added sodium borohydride (0.89 g) withice-cooling and the mixture was stirred as such for 0.5 hour. To thereaction solution was added an aqueous ammonium chloride solution wasadded and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain ethyl3-hydroxy-4-[3-(methoxymethoxy)phenyl]butanoate as an oily matter.

To a solution of the obtained oily matter and triethylamine (4.93 ml) inethyl acetate (100 ml) was added dropwise a solution of methanesulfonylchloride (3.24 g) in ethyl acetate (30 ml) with ice-cooling and themixture was stirred as such for 0.5 hour. The produced precipitate wasfiltered and washed with ethyl acetate. The solvent of the obtainedfiltrate was distilled off under reduced pressure to obtain a crudeproduct of methanesulfonic ester as an oily matter. The obtained oilymatter was dissolved in tetrahydrofuran (60 ml),1,8-diazabicyclo[5.4.0]-7-undecene (3.95 g) was added at roomtemperature, and then the mixture was stirred as such for 1 hour. Thesolvent of the reaction solution was distilled off under reducedpressure and the obtained residue was subject to silica gel columnchromatography (hexane:ethyl acetate=6:1) to obtain crude ethyl4-[3-(methoxymethoxy)phenyl]-2-butenate as an oily matter.

A solution of the obtained oily matter in toluene (30 ml)-ethanol (5 ml)was hydrogenated at room temperature under normal pressure using achlorotris(triphenylphosphine) rhodium (I) (0.65 g) as a catalystovernight. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=6:1) to obtain an objective product(3.67 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.87-2.03 (2H, m), 2.32 (2H, t), 2.63(2H, t), 3.48 (3H, s), 4.13 (2H, q), 5.17 (2H, s), 6.81-6.91 (3H, m),7.20 (1H, dd).

Reference Example 35 Ethyl 4-(3-hydroxyphenyl)butanoate

To a solution of ethyl 4-[3-(methoxymethoxy)phenyl]butanoate (3.67 g) inethanol (50 ml) was added concentrated hydrochloric acid (3 ml) at roomtemperature and the mixture was stirred at room temperature overnight.The solvent of the mixture was distilled off under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to obtain an objective product (2.72 g) as anoily matter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.89-1.99 (2H, m), 2.32 (2H, t), 2.60(2H, t), 4.12 (2H, q), 4.97 (1H, s), 6.65-6.68 (2H, m), 6.74 (1H, d),7.14 (1H, dd).

Reference Example 36 Ethyl 3-(4-hydroxy-2-methylphenyl)propionate

To a suspension of sodium hydride (1.33 g) in tetrahydrofuran (100 ml)was added dropwise ethyl diethylphosphonoacetate (4.16 ml) withice-cooling and the mixture was stirred for 30 minutes. To the reactionsolution was added dropwise a solution of 2-methyl 4-benzyloxybenzaldehyde (5.0 g) in tetrahydrofuran (25 ml) and the mixture wasstirred at 0° C. for 2 hours and at room temperature for 1 hour. 1 Nhydrochloric acid was added thereto and the mixture was diluted withethyl acetate. Then, the organic layer was separated and then washedwith a saturated sodium bicarbonate solution, water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filteredand then concentrated under reduced pressure. The obtained residue wassubject to silica gel column chromatography (hexane:ethyl acetate=3:1)and the obtained-compound was dissolved in ethanol (60 ml). After 10%palladium-carbon (2 g) was added under nitrogen gas stream, theatmosphere was substituted with a hydrogen atmosphere and the mixturewas stirred at room temperature for 5 hours. Insolubles were filteredand the residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to obtain an objective product (4.43 g) as anoily matter.

¹H-NMR (CDCl₃) δ 1.24 (3H, t), 2.25 (3H, s), 2.50-2.56 (2H, m), 2.85(2H, dd), 4.13 (2H, q), 5.21 (1H, d), 6.57 (1H, dd), 6.62 (1H, d), 6.97(1H, d).

Reference Example 37 [4-(Benzyloxy)-2-methylphenyl]acetonitrile

A suspension of potassium tert-butoxide (4.94 g) in dimethoxyethane (100ml) was cooled to −78° C., toluenesulfonylmethyl isocyanide (4.73 g) wasadded thereto, and then the mixture was stirred for 5 minutes. Then, asolution of 2-methyl 4-benzyloxybenzaldehyde (4.99 g) in dimethoxyethane(50 ml) was added thereto and the mixture was stirred at −78° C. for 1hour and at room temperature for 1 hour. Methanol was added thereto andthe mixture was heated under reflux for 1 hour. After standing to cool,the reaction solution was poured into a saturated aqueous ammoniumchloride solution and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, filtered and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1 to 3:1) to obtain an objectiveproduct (3.04 g) as crystals.

Melting point 51-52° C.; ¹H-NMR (CDCl₃) δ 2.30 (3H, s), 3.58 (2H, s),5.04 (2H, s), 6.77-6.79 (1H, m), 6.83 (1H, s), 7.22 (1H, d), 7.31-7.43(5H, m).

Reference Example 38 Methyl [4-(benzyloxy)-2-methylphenyl]acetate

To a solution of [4-(benzyloxy)-2-methylphenyl]acetonitrile (2.97 g) intetrahydrofuran (30 ml)-ethanol (30 ml) was added 8 N sodium hydroxide(30 ml) and the mixture was heated under reflux overnight. The mixturewas acidified with 6 N hydrochloric acid, and then extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, filtered, and then concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide (50ml), and potassium carbonate (3.46 g) and iodomethane (1.8 ml) wereadded thereto. The mixture was stirred at room temperature overnight andthen diluted with ethyl acetate and washed with water and saturatedbrine. The mixture was dried over anhydrous magnesium sulfate, filtered,and then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane-ethyl acetate=5:1) to obtainan objective product (1.13 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 3.57 (2H, s), 3.67 (3H, s), 5.03 (2H, s),6.74-6.83 (2H, m), 7.10 (1H, d), 7.30-7.45 (5H, m).

Reference Example 39 Methyl (4-hydroxy-2-methylphenyl)acetate

To a solution of methyl [4-(benzyloxy)-2-methylphenyl]acetate (1.13 g)in methanol (20 ml) was added 10% palladium-carbon (0.6 g) undernitrogen gas stream, the atmosphere was substituted with a hydrogenatmosphere and the mixture was stirred at room temperature for 2 days.Insolubles were filtered and the solvent was distilled off under reducedpressure to obtain an objective product (0.71 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.24 (3H, s), 3.56 (2H, s), 3.69 (3H, s) 6.61-6.62 (2H,m), 7.02 (1H, d).

Reference Example 40 [2-Methoxy-4-(methoxymethoxy)phenyl]acetonitrile

A suspension of potassium tert-butoxide (4.69 g) in dimethoxyethane (30ml) was cooled to −78° C., toluenesulfonylmethyl isocyanide (4.49 g) wasadded thereto, and then the mixture was stirred for 5 minutes. Then, asolution of 2-methoxy-4-(methoxymethoxy)benzaldehyde (4.10 g) indimethoxyethane (30 ml) was added, and the mixture was stirred at −78°C. for 1 hour and at room temperature for 1 hour. Methanol was added andheated under reflux for 1 hour. After standing to cool, the reactionsolution was poured into a saturated aqueous ammonium chloride solutionand the aqueous layer was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, filtered, and then concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=5:1 to 2:1) to obtain an objective product (2.13 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 3.48 (3H, s), 3.61 (2H, s), 3.84 (3H, s), 5.17 (2H, s),6.58-6.66 (2H, m), 7.22 (1H, d).

Reference Example 41 Methyl (4-hydroxy-2-methoxyphenyl)acetate

To a solution of [2-methoxy-4-(methoxymethoxy)phenyl]acetonitrile (2.13g) in ethanol (10 ml) was added 8 N sodium hydroxide (10 ml) and themixture was heated under reflux overnight. After completing thereaction, the mixture was acidified with 6 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andthen concentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (50 ml). Potassium carbonate (2.14 g) andiodomethane (1.75 g) were added thereto, and the mixture was stirred atroom temperature for 3 days. After diluting with ethyl acetate, theorganic layer was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, filtered, and thenconcentrated under reduced pressure. The residue was dissolved inmethanol (10 ml) and 1 ml of concentrated hydrochloric acid was added.The mixture was heated under reflux overnight. The reaction mixture wasconcentrated under reduced pressure and subjected to azeotropy withtoluene to remove moisture. Then, the residue was purified by silica gelcolumn chromatography (hexane ethyl acetate=5:1 to 2:1) to obtain anobjective product (1.32 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.55 (2H, s), 3.70 (3H, s), 3.71 (3H, s), 5.95 (1H, brs), 6.24-6.32 (2H, m), 6.94 (1H, d).

Reference Example 42 Methyl(4-methyl-2-mercapto-1,3-thiazol-5-yl)acetate

To a solution of (4-methyl-2-mercapto-1,3-thiazol-5-yl) acetic acid (10g) in methanol (200 ml) was added concentrated sulfuric acid (0.5 ml)and the mixture was heated under reflux overnight. After methanol wasdistilled off under reduced pressure, the reaction mixture was dilutedwith ethyl acetate and washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andthen concentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to obtain an objective product(7.18 g) as crystals. Melting point 139-140° C.; ¹H-NMR (CDCl₃) δ 2.18(3H, s), 3.51 (2H, s), 3.74 (3H, s), 12.15 (1H, br s).

Reference Example 43 Benzyl 6-(benzyloxy)-2-naphthoate

To a solution of 6-hydroxy-2-naphthoic acid (17.9 g) inN,N-dimethylformamide (200 ml) was added potassium carbonate (32.9 g)and benzyl bromide (22.6 ml) and the mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate and washed with water and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, filtered, and then concentratedunder reduced pressure. The residue was purified by recrystallization(hexane-ethyl acetate) to obtain an objective product (26.1 g) ascrystals.

Melting point 97-98° C.; ¹H-NMR (CDCl₃) δ 5.18 (2H, s), 5.40 (2H, s),7.21-7.27 (2H, m), 7.31-7.49 (10H, m), 7.72 (1H, d), 7.84 (1H, d), 8.04(1H, dd), 8.54 (1H, s).

Reference Example 44 [6-(Benzyloxy)-2-naphthyl]methanol

To a suspension of aluminum lithium hydride (2.32 g) in tetrahydrofuran(100 ml) was added dropwise a solution of benzyl6-(benzyloxy)-2-naphthoate (15 g) in tetrahydrofuran (50 ml) withice-cooling to and the mixture was stirred at 0° C. for 1 hour. Water(2.4 ml), 15% sodium hydroxide (2.4 ml) and water (7.2 ml) were addedand the reaction was completed. The mixture was stirred at roomtemperature for 30 minutes. Insolubles were filtered and washed withtetrahydrofuran. The filtrate was concentrated under reduced pressureand the residue was purified by recrystallization (hexane-ethyl acetate)to obtain an objective product (10.1 g) as crystals.

Melting point 141-142° C.; ¹H-NMR (CDCl₃) δ 4.79 (2H, s), 5.16 (2H, s),7.21-25 (2H, m), 7.33-7.51 (6H, m), 7.69-7.75 (3H, m).

Reference Example 45 6-(Benzyloxy)-2-naphthaldehyde

To a solution of [6-(benzyloxy)-2-naphthyl]methanol (5 g) intetrahydrofuran (60 ml) was added manganese dioxide (15 g) and themixture was stirred at room temperature overnight. Insolubles werefiltered through Celite and washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure and the residue was purified byrecrystallization (hexane-ethyl acetate) to obtain an objective product(4.08 g) as crystals.

Melting point 107-108° C.; ¹H-NMR (CDCl₃) δ 5.21 (2H, s) 7.24-7.50 (7H,m), 7.78 (1H, d), 7.88-7.92 (2H, m), 8.24 (1H, s), 10.08 (1H, s).

Reference Example 46 Ethyl (E)-3-[6-(benzyloxy)-2-naphthyl]acrylate

To a suspension of sodium hydride (0.46 g) in tetrahydrofuran (20 ml)was added dropwise ethyl diethylphosphonoacetate (4.16 ml) withice-cooling and the mixture was stirred for 30 minutes. To the reactionsolution was added dropwise a solution of 6-(benzyloxy)-2-naphthaldehyde(2.0 g) in tetrahydrofuran (15 ml) and the mixture was stirred at 0° C.for 2 hours. 1 N hydrochloric acid was added thereto and diluted inethyl acetate. The organic layer was separated and washed with asaturated sodium bicarbonate solution, water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andthen concentrated under reduced pressure. The obtained residue waspurified by recrystallization (hexane-ethyl acetate) to obtain anobjective product (2.09 g) as crystals.

Melting point 110-112° C.; ¹H-NMR (CDCl₃) δ 1.35 (3H, t) 4.28 (2H, q),5.19 (2H, s), 6.48 (1H, d), 7.22-7.27 (2H, m), 7.34-7.50 (5H, m),7.60-7.85 (5H, m).

Reference Example 47 Ethyl 3-(6-hydroxy-2-naphthyl)propionate

Ethyl (E)-3-[6-(benzyloxy)-2-naphthyl]acrylate (1.67 g) was dissolved inethanol (15 ml) and 10% palladium-carbon (0.5 g) was added undernitrogen gas stream, the atmosphere was substituted with a hydrogenatmosphere and the mixture was stirred at room temperature overnight.Insolubles were filtered, and then the filtrate was purified by silicagel column chromatography (hexane:ethyl acetate=5:1 to 2:1) to obtain anobjective product (0.86 g) as crystals.

Melting point 90-91° C.; ¹H-NMR (CDCl₃) δ 1.32 (3H, t), 2.70 (2H, t),3.07 (2H, t), 4.14 (2H, q), 5.54 (1H, s), 7.03-7.08 (2H, m), 7.24-7.29(1H, m), 7.55-7.65 (3H, m).

Reference Example 48 2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]pentanoicacid

In the same manner as in Reference Example 12, an objective product wasobtained from 1-[5-(4-fluorophenyl)-2-methyl-3-furyl]butan-1-ol obtainedin Reference Example 14(1).

Melting point 96-97° C.; ¹H-NMR (CDCl₃) δ 0.92 (3H, t), 1.23-1.42 (2H,m), 1.62-1.80 (1H, m), 1.89-2.07 (1H, m), 2.32 (3H, s), 3.45 (1H, t),6.54 (1H, s), 7.03 (2H, t), 7.57 (2H, dd).

Reference Example 49 2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]pentan-1-ol

In the same manner as in Reference Example 13, an objective product wasobtained from 2-[5-(4-fluorophenyl)-2-methyl-3-furyl]pentanoic acidobtained in Reference Example 12(2).

An oily matter; ¹H-NMR (CDCl₃) δ 0.89 (3H, t), 1.19-1.62 (5H, m), 2.32(3H, s), 2.66-2.76 (1H, m), 3.58 (1H, dd), 3.71 (1H, dd), 6.40 (1H, s),7.04 (2H, t), 7.57 (2H, dd).

Reference Example 503-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzaldehyde

To a solution of{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (4.12 g),3-hydroxybenzaldehyde (2.4 g) and tributylphosphine (4.9 g) intetrahydrofuran (250 ml) was added 1,1′-(azodicarbonyl)dipiperidine (6.1g) at room temperature and the mixture was stirred overnight. Thesolvent of the reaction solution was distilled off under reducedpressure and diisopropyl ether was added. The precipitate was filteredoff and washed with diisopropyl ether. The solvent of the filtrate wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1to 9:1) to obtain an objective product (4.30 g) as a solid matter.

Melting point 85-86° C.; ¹H-NMR (CDCl₃) δ 2.44 (3H, s), 4.95 (2H, s),6.80 (1H, s), 7.22-7.28 (1H, m), 7.47-7.52 (3H, m), 7.60 (2H, d), 7.72(2H, d), 10.00 (1H, s).

Reference Example 51S-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thioacetate

To a solution of3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzaldehyde(2.52 g) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodiumborohydride (0.26 g) with ice-cooling and the mixture was stirred for0.5 hour at room temperature. The reaction solution was concentratedunder reduced pressure, poured into water and then extracted with ethylacetate twice. The collected organic layer was dried over anhydrousmagnesium sulfate, passed through silica gel, and then the solvent wasdistilled off under reduced pressure to obtain an oily matter.

To a solution of the obtained oily matter and triethylamine (1.5 ml) inethyl acetate (30 ml) was added dropwise methanesulfonyl chloride (0.65ml) with ice-cooling and the mixture was stirred as such for 0.5 hour.The produced precipitate was filtered and washed with ethyl acetate. Thesolvent of the obtained filtrate was distilled off under reducedpressure to obtain an oily matter. The obtained oily matter wasdissolved in N,N-dimethylformamide (20 ml) and potassium thioacetate(1.2 g) was added at room temperature. The mixture was stirred as suchfor 3 days. The reaction solution was poured into water and twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=6:1) and crystallized fromhexane to obtain an objective product (2.50 g) as crystals. Meltingpoint 90-91° C.; ¹H-NMR (CDCl₃) δ 2.35 (3H, s), 2.41 (3H, s), 4.10 (2H,s), 4.85 (2H, s), 6.78 (1H, s), 6.83-6.91 (3H, m), 7.22 (1H, t), 7.59(2H, d), 7.70 (2H, d).

Reference Example 52 [4-Fluoro-3-(methoxymethoxy)phenyl]methanol

To a solution of 4-fluoro-3-hydroxybenzoic acid (9.81 g) intetrahydrofuran (100 ml) was added N-ethyldiisopropylamine (17.9 g) atroom temperature and the mixture was stirred for 0.5 hour.Chloromethylmethyl ether (12.6 g) was added thereto at room temperatureand the mixture was stirred at 60° C. overnight. The reaction solutionwas poured into water and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to obtain an oilymatter.

To a suspension of aluminum lithium hydride (3.6 g) in tetrahydrofuran(100 ml) was added dropwise a solution of the obtained oily matter intetrahydrofuran (100 ml) with ice-cooling and the mixture was stirred atroom temperature overnight. The reaction solution was ice-cooled andwater (3.5 ml), a 15% aqueous sodium hydroxide solution (3.5 ml) andwater (9 ml) were sequentially added dropwise. Excess aluminum lithiumhydride was decomposed and the resultant was stirred as such at roomtemperature for 2 hours. The produced precipitate was filtered off, andwashed with ethyl acetate. The solvent of the collected filtrate wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (ethyl acetate) to obtainan objective product (11.3 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.75 (1H, t), 3.53 (3H, s), 4.63 (2H, d), 5.22 (2H, s),6.95 (1H, ddd), 7.06 (1H, dd), 7.20 (1H, dd).

Reference Example 53 Ethyl{[4-fluoro-3-(methoxymethoxy)benzyl]thio}acetate

In the same manner as in Reference Example 24, an objective product wasobtained from [4-fluoro-3-(methoxymethoxy)phenyl]methanol.

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.07 (2H, s), 3.52 (3H,s), 3.78 (2H, s), 4.18 (2H, q), 5.21 (2H, s), 6.92 (1H, ddd), 7.02 (1H,dd), 7.18 (1H, dd).

Reference Example 54 Ethyl [(4-fluoro-3-hydroxybenzyl)thio]acetate

In the same manner as in Reference Example 25, an objective product wasobtained from ethyl {[4-fluoro-3-(methoxymethoxy)benzyl]thio}acetate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 3.06 (2H, s) 3.75 (2H,s), 4.18 (2H, q), 5.22 (1H, d), 6.81 (1H, ddd), 6.97-7.03 (2H, m).

Reference Example 55 (2-Fluoro-5-methoxyphenyl)methanol

In the same manner as in Reference Example 23, an objective product wasobtained from 2-fluoro-5-methoxybenzaldehyde.

An oily matter; ¹H-NMR (CDCl₃) δ 1.83 (1H, t), 3.79 (3H, s), 4.73 (2H,d), 6.76 (1H, td), 6.93-6.99 (2H, m).

Reference Example 56 Ethyl [(2-fluoro-5-methoxybenzyl)thio]acetate

In the same manner as in Reference Example 24, an objective product wasobtained from (2-fluoro-5-methoxyphenyl)methanol.

An oily matter; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 3.16 (2H, s), 3.79 (3H,s), 3.83 (2H, s), 4.19 (2H, q), 6.71-6.79 (1H, m), 6.89 (1H, dd), 6.98(1H, t).

Reference Example 57 Ethyl [(2-fluoro-5-hydroxybenzyl)thio]acetate

To a suspension of aluminum chloride (3.6 g) in toluene (20 ml) wasadded 1-octanethiol (12.7 g) at room temperature and the mixture wasstirred for 0.5 hour. A solution of ethyl[(2-fluoro-5-methoxybenzyl)thio]acetate (2.81 g) in toluene (20 ml) wasadded thereto at room temperature, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was poured into icedwater and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane to hexane:ethylacetate=3:1) to obtain an objective product (1.97 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.15 (2H, s), 3.80 (2H, d), 4.18 (2H, q),5.04 (1H, s), 6.69 (1H, td), 6.83 (1H, dd), 6.91 (1H, t).

Reference Example 581-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethanone

To a solution of 1,8-azabicyclo[5.4.0]-7-undecene (18.8 g) in toluene(50 ml) was added dropwise a solution of acetyl acetone (1.24 g) intoluene (30 ml) with ice-cooling. The reaction solution was stirred assuch for 10 minutes, and then a solution of2-bromo-4′-(trifluoromethyl)acetophenone (33.1 g) in toluene (80 ml) wasadded thereto with ice-cooling. The mixture was further stirred at roomtemperature for 2 hours. The produced precipitate was filtered andwashed with toluene. The obtained toluene solution was passed throughsilica gel and the silica gel was washed with ethyl acetate-hexane(1:1). The collected solution was concentrated under reduced pressure,ethyl acetate-hexane was removed to obtain the toluene solution. To thetoluene solution was added 4-toluenesulfonic acid.1 hydrate (2.4 g) andthe mixture was stirred at 100° C. for 1.5 hours. The reaction solutionwas washed with an aqueous sodium hydrogen carbonate solution and theaqueous layer was extracted with ethyl acetate. The organic layer wascollected and dried over magnesium sulfate and the solvent was distilledoff under reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=15:1) andcrystallized from cold methanol to obtain an objective product (10.7 g)as crystals.

Melting point 87-88° C.; ¹H-NMR (CDCl₃) δ 2.48 (3H, s), 2.69 (3H, s),6.98 (1H, s), 7.64 (2H, d), 7.75 (2H, d).

Reference Example 59 [4-Fluoro-3-(methoxymethoxy)phenyl]acetonitrile

To a solution of [4-fluoro-3-(methoxymethoxy)phenyl]methanol (2.35 g),acetone cyanohydrin (1.61 g) and tributylphosphine (3.83 g) intetrahydrofuran (70 ml) was added a solution (8.30 g) of 40% diethylazodicarboxylate in toluene at room temperature and the mixture wasstirred overnight. The solvent of the reaction solution was distilledoff under reduced pressure and diisopropyl ether was added. Theprecipitate was filtered off and washed with diisopropyl ether. Thesolvent of the filtrate was distilled off under reduced pressure and theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=9:1 to 6:1) to obtain an objective product (2.27g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.53 (3H, s), 3.71 (2H, s), 5.23 (2H, s), 6.91-6.99(1H, m), 7.05-7.18 (2H, m).

Reference Example 60 Ethyl (4-fluoro-3-hydroxyphenyl)acetate

A mixture of [4-fluoro-3-(methoxymethoxy)phenyl]acetonitrile (2.27 g),sodium hydroxide (2.3 g), water (8 ml) and ethanol (30 ml) was stirredat 80° C. overnight. The solvent of the reaction solution was distilledoff under reduced pressure and diluted with water. The reaction solutionwas acidified with dilute hydrochloric acid and twice extracted withethyl acetate. The collected organic layer was dried over anhydroussodium sulfate and the solvent was distilled off under reduced pressureto obtain an oily matter. The obtained oily matter was dissolved inethanol (40 ml) and concentrated hydrochloric acid (0.5 ml) was added.The reaction mixture was stirred at 80° C. overnight. The reactionsolution was diluted with water and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous sodium sulfate andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=6:1 to 3:1) to obtain an objective product (1.50 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 3.53 (2H, s), 4.15 (2H, q), 5.17 (1H, d),6.76 (1H, ddd), 6.94 (1H, dd), 7.01 (1H, dd).

Reference Example 61 (2-Fluoro-5-methoxyphenyl)acetonitrile

In the same manner as in Reference Example 59, an objective product wasobtained from (2-fluoro-5-methoxyphenyl)methanol obtained in ReferenceExample 55. An oily matter; ¹H-NMR (CDCl₃) δ 3.74 (2H, s), 3.80 (3H, s),6.82 (1H, td), 6.94 (1H, dd), 7.01 (1H, t).

Reference Example 62 Ethyl (2-fluoro-5-hydroxyphenyl)acetate

A mixture of (2-fluoro-5-methoxyphenyl)acetonitrile (1.91 g), sodiumhydroxide (2.3 g), water (7 ml) and ethanol (30 ml) were stirred at 80°C. overnight. The solvent of the reaction solution was distilled offunder reduced pressure and diluted with water. The reaction solution wasacidified with dilute hydrochloric acid and twice extracted with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure toobtain an oily matter. The obtained oily matter was dissolved in ethanol(40 ml) and concentrated hydrochloric acid (0.5 ml) was added. Thereaction mixture was stirred at 80° C. overnight. The reaction solutionwas diluted with water and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous sodium sulfate and thesolvent was distilled off under reduced pressure to obtain an oilymatter.

To a suspension of aluminum chloride (3.9 g) in toluene (30 ml) wasadded 1-octanethiol (13.5 g) at room temperature and the mixture wasstirred for 0.5 hour. A solution of the obtained oily matter in toluene(20 ml) was added at room temperature and the mixture was stirred atroom temperature for 2 hours. The reaction solution was poured into icedwater and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane to hexane:ethylacetate=3:1) to obtain an objective product (1.84 g) as a solid matter.Melting point 85-87° C.; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 3.61 (2H, d),4.19 (2H, q), 5.00 (1H, s), 6.65-6.73 (2H, m), 6.91 (1H, t).

Reference Example 63 [3-(Methoxymethoxy)-2-methylphenyl]methanol

In the same manner as in Reference Example 52, an objective product wasobtained from 3-hydroxy-2-methylbenzoic acid.

An oily matter; ¹H-NMR (CDCl₃) δ 1.58 (1H, t), 2.26 (3H, s), 3.49 (3H,s), 4.69 (2H, d), 5.20 (2H, s), 7.03 (2H, d), 7.14 (1H, dd).

Reference Example 64 Ethyl [(3-hydroxy-2-methylbenzyl)thio]acetate

In the same manner as in Reference Example 24, ethyl{[3-(methoxymethoxy)-2-methylbenzyl]thio}acetate was obtained from[3-(methoxymethoxy)-2-methylphenyl]methanol, and the obtained matter wasfurther processed by the method as described in Reference Example 25 toobtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.31 (3H, t), 2.27 (3H, s) 3.12 (2H,s), 3.85 (2H, s), 4.20 (2H, q), 4.80 (1H, s), 6.71 (1H, d), 6.83 (1H,d), 7.00 (1H, t).

Reference Example 65[2-Ethoxy-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]methanol

A suspended matter (2.98 g) of 60% sodium hydride in liquid paraffin wastwice washed with hexane and then suspended in tetrahydrofuran (30 ml).A solution of methyl 2-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)benzoate(10.9 g) in tetrahydrofuran (80 ml) was added with ice-cooling and themixture was stirred for 30 minutes. Ethyl iodide (4.16 ml) was addedthereto with ice-cooling and the mixture was stirred at 60° C. for 2days. The reaction solution was poured into water and twice extractedwith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain an oily matter.

To a suspension of aluminum lithium hydride (2.5 g) in tetrahydrofuran(100 ml) was added dropwise a solution of the obtained oily matter intetrahydrofuran (100 ml) with ice-cooling and the mixture was stirred atroom temperature overnight. The reaction solution was ice-cooled, andwater (2.5 ml), a 15% aqueous sodium hydroxide solution (2.5 ml) andwater (6 ml) were sequentially added dropwise. Excess aluminum lithiumhydride was decomposed and then the resulting mixture was stirred atroom temperature for 2 hours. The obtained precipitate was filtered offand then washed with ethyl acetate. The solvent of the collectedfiltrate was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=6:1 to 2:1) to obtain an objective product (6.64 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.42 (3H, t), 1.53-2.05 (6H, m), 2.49 (1H, t),3.53-3.64 (1H, m), 3.87-4.00 (1H, m), 4.04 (2H, q), 4.65 (2H, d), 5.31(1H, t), 6.78 (1H, d), 6.91-7.10 (2H, m).

Reference Example 66 Ethyl [(2-ethoxy-5-hydroxybenzyl)thio]acetate

In the same manner as in Reference Example 24, ethyl{[2-ethoxy-5-(tetrahydro-2H-pyran-2-yloxy)benzyl]thio}acetate wasobtained from [2-ethoxy-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]methanol,and the obtained matter was further processed by the method as describedin Reference Example 25 to obtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 1.40 (3H, t), 3.17 (2H,s), 3.80 (2H, s), 4.00 (2H, q), 4.19 (2H, q), 4.69 (1H, s), 6.66-6.81(3H, m).

Reference Example 67 Ethyl (3-hydroxy-2-methylphenyl)acetate

In the same manner as in Reference Example 59,[3-(methoxymethoxy))-2-methylphenyl]acetonitrile was obtained from[3-(methoxymethoxy)-2-methylphenyl]methanol, and the obtained matter wasfurther processed by the method as described in Reference Example 60 toobtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 2.19 (3H, s), 3.64 (2H,s), 4.16 (2H, q), 4.85 (1H, s), 6.69 (1H, d), 6.79 (1H, d), 7.02 (1H,t).

Reference Example 68 [3-(Methoxymethoxy)-4-methylphenyl]methanol

In the same manner as in Reference Example 52, an objective product wasobtained from 3-hydroxy-4-methylbenzoic acid.

An oily matter; ¹H-NMR (CDCl₃) δ 1.65 (1H, t), 2.24 (3H, s), 3.49 (3H,s), 4.64 (2H, d), 5.22 (2H, s), 6.91 (1H, dd), 7.06 (1H, s), 7.14 (1H,d).

Reference Example 69 Ethyl [(3-hydroxy-4-methylbenzyl)thio]acetate

In the same manner as in Reference Example 24, ethyl{[3-(methoxymethoxy)-4-methylbenzyl]thio}acetate was obtained from[3-(methoxymethoxy)-4-methylphenyl]methanol, and the obtained matter wasfurther processed by the method as described in Reference Example 25 toobtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 2.23 (3H, s), 3.07 (2H,s), 3.75 (2H, s), 4.18 (2H, q), 4.79 (1H, s), 6.78 (1H, s), 6.80 (1H,d), 7.06 (1H, d).

Reference Example 70 1-(3-Methoxyphenyl)butan-1-ol

To a solution of 3-methoxybenzaldehyde (13.1 g) in tetrahydrofuran (100ml) was added dropwise a 2 N solution (72 ml) of propylmagnesium bromidein tetrahydrofuran at −78° C. and the reaction solution was stirred at−50° C. for 1 hour. The reaction solution was poured into an aqueousammonium chloride solution and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=6:1) to obtain an objective product (14.8 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.93 (3H, t), 1.21-1.53 (2H, m), 1.61-1.83 (2H, m),1.82 (1H, d), 3.82 (3H, s), 4.62-4.71 (1H, m), 6.79-6.84 (1H, m),6.91-6.94 (2H, m), 7.26 (1H, t).

Reference Example 71 S-[1-(3-methoxyphenyl)butyl]thioacetate

To a solution of 1-(3-methoxyphenyl)butan-1-ol (3.89 g) andtriethylamine (4.5 ml) in ethyl acetate (30 ml) was added dropwisemethanesulfonyl chloride (2.0 ml) with ice-cooling, and the mixture wasstirred as such for 0.5 hour. The produced precipitate was filtered andwashed with ethyl acetate. The solvent of the obtained filtrate wasdistilled off under reduced pressure to obtain an oily matter. Theobtained oily matter was dissolved in N,N-dimethylformamide (15 ml) andpotassium thioacetate (3.7 g) was added at room temperature. Thereaction mixture was stirred at 50° C. overnight. The reaction solutionwas poured into water and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=15:1) to obtain an objective product (4.41 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.90 (3H, t), 1.17-1.46 (2H, m), 1.89 (2H, q), 2.29(3H, s), 3.80 (3H, s), 4.55 (1H, t), 6.74-6.90 (3H, m), 7.22 (1H, t)

Reference Example 72 Ethyl {[1-(3-methoxyphenyl)butyl]thio}acetate

To a solution of S-[1-(3-methoxyphenyl)-butyl]thioacetate (1.89 g) inmethanol (50 ml) was added sodium hydroxide (0.32 g) at room temperatureand the mixture was stirred as such for 1 hour. The solvent of themixture was distilled off under reduced pressure to obtain a solidmatter. The obtained solid matter was dissolved in N,N-dimethylformamide(20 ml) and ethyl bromoacetate (1.1 ml) was added at room temperature.The reaction mixture was stirred at 60° C. for 1 hour. The reactionsolution was poured into water and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane:ethyl acetate=9:1) to obtain an objective product (1.60 g) as anoily matter.

¹H-NMR (CDCl₃) δ 0.88 (3H, t), 1.22-1.39 (2H, m), 1.26 (3H, t),1.73-1.89 (2H, m), 2.90 (1H, d), 3.00 (1H, d), 3.81 (3H, s), 3.96 (1H,dd), 4.13 (2H, dq), 6.76-6.80 (1H, m), 6.87-6.90 (2H, m), 7.22 (1H, t).

Reference Example 73 Ethyl {[1-(3-hydroxyphenyl)butyl]thio}acetate

In the same manner as in Reference Example 57, an objective product wasobtained from ethyl {[1-(3-methoxyphenyl)butyl]thio}acetate.

An oily matter; ¹H-NMR (CDCl₃) δ 0.88 (3H, t), 1.21-1.40 (2H, m), 1.26(3H, t), 1.75-1.88 (2H, m), 2.91 (1H, d), 3.02 (1H, d), 3.94 (1H, t),4.13 (2H, q), 4.90 (1H, s), 6.69-6.75 (1H, m), 6.82 (1H, t), 6.87 (1H,d), 7.18 (1H, t).

Reference Example 74 4-Chloro-3-(methoxymethoxy)benzyl acetate

To a solution of 2-chloro-4-methylphenol (5.19 g) in tetrahydrofuran (50ml) was added N-ethyldiisopropylamine (8.3 ml) at room temperature andthe mixture was stirred for 0.5 hour.

Chloromethylmethyl ether (3.8 g) was added thereto at room temperatureand the mixture was stirred at 60° C. overnight. The reaction solutionwas poured into water and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andpassed through silica gel. The solvent was distilled off under reducedpressure to obtain an oily matter.

A solution of the obtained oily matter, N-bromosuccinimide (6.5 g) and2,2′-azobis(isobutyronitrile) (0.5 g) in tetrachloromethane (30 ml) washeated under reflux for 3 hours. After the reaction solution was cooledto room temperature, the precipitate was filtered off and then washedwith diethyl ether. The solvent of the collected filtrate was distilledoff under reduced pressure to obtain an oily matter. The obtained oilymatter was dissolved in N,N-dimethylformamide (50 ml) and sodium acetate(6.0 g) was added at room temperature. The mixture was stirred at 60° C.overnight. The reaction solution was poured into water and twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=9:1 to 6:1) to obtain anobjective product (2.29 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.11 (3H, s), 3.53 (3H, s), 5.04 (2H, s), 5.26 (2H, s),6.95 (1H, dd), 7.16 (1H, d), 7.35 (1H, d).

Reference Example 75 [4-Chloro-3-(methoxymethoxy)phenyl]methanol

A mixture of 4-chloro-3-(methoxymethoxy)benzyl acetate (2.29 g), a 1 Naqueous sodium hydroxide solution (14 ml), methanol (20 ml) andtetrahydrofuran (20 ml) was stirred at room temperature overnight. Thereaction solution was concentrated, diluted with water and twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and passed through silica gel. The solvent wasdistilled off under reduced pressure to obtain an objective product(1.92 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.82 (1H, br t), 3.52 (3H, s), 4.65 (2H, d), 5.26 (2H,s), 6.95 (1H, tdd), 7.18 (1H, d), 7.34 (1H, d).

Reference Example 76 Ethyl [(4-chloro-3-hydroxybenzyl)thio]acetate

In the same manner as in Reference Example 24, ethyl{[4-chloro-3-(methoxymethoxy)benzyl]thio}acetate was obtained from[4-chloro-3-(methoxymethoxy)phenyl]methanol, and the obtained matter wasfurther processed by the method as described in Reference Example 25 toobtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 3.06 (2H, s), 3.76 (2H,s), 4.18 (2H, q), 5.53 (1H, s), 6.85 (1H, dd), 7.01 (1H, d), 7.25 (1H,d).

Reference Example 77 3-(Acetyloxy)-5-methylbenzyl acetate

To a solution of 3,5-dimethylphenol (10.1 g) in pyridine (50 ml) wasadded acetyl chloride (7.8 g) with ice-cooling and the mixture wasstirred at room temperature overnight. The reaction solution was pouredinto water and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained residue was subjectto silica gel column chromatography (hexane:ethyl acetate=6:1) to obtainan oily matter.

A solution of the obtained oily matter, N-bromosuccinimide (14.8 g) and2,2′-azobis(isobutyronitrile) (0.3 g) in tetrachloromethane (50 ml) washeated under reflux for 1 hour. After the reaction solution was cooledto room temperature, the precipitate was filtered off and then washedwith diethyl ether. The solvent of the collected filtrate was distilledoff under reduced pressure to obtain an oily matter. The obtained oilymatter was dissolved in N,N-dimethylformamide (50 ml) and sodium acetate(13.6 g) was added thereto at room temperature. The mixture was stirredat 60° C. for 6 hours. The reaction solution was poured into water andtwice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=6:1 to 3:1) toobtain an objective product (9.87 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.10 (3H, s), 2.29 (3H, s), 2.36 (3H, s), 5.05 (2H, s),6.86 (1H, s), 6.88 (1H, d), 7.02 (1H, d).

Reference Example 78 [3-(Methoxymethoxy)-5-methylphenyl]methanol

3-(Acetyloxy)-5-methylbenzyl acetate (9.87 g) was dissolved in methanol(20 ml) and tetrahydrofuran (30 ml).

A solution of a 0.5 N aqueous sodium hydroxide solution (89 ml) wasadded dropwise with ice-cooling and the mixture was stirred as such for1 hour. The reaction solution was concentrated, diluted with water, andtwice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous sodium sulfate and passed through silica gel. Thesolvent was distilled off under reduced pressure to obtain an oilymatter.

To a solution of the obtained oily matter in tetrachloromethane (50 ml)was added N-ethyldiisopropylamine (4.4 ml) with ice-cooling and themixture was stirred for 0.5 hour. Chloromethylmethyl ether (1.9 ml) wasadded thereto at 0° C. and the mixture was stirred at 60° C. overnight.The reaction solution was poured into water and twice extracted withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasdistilled off under reduced pressure to obtain an oily matter. A mixtureof the obtained oily matter, a 1 N aqueous sodium hydroxide solution (40ml), methanol (30 ml) and tetrahydrofuran (30 ml) was stirred at roomtemperature overnight. The reaction solution was concentrated, dilutedwith water, and twice extracted with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas distilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=3:1to 2:1) to obtain an objective product (2.11 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.64 (1H, t), 2.33 (3H, s), 3.47 (3H, s), 4.63 (2H, d),5.16 (2H, s), 6.78 (1H, s), 6.83 (1H, s), 6.84 (1H, s).

Reference Example 79 Ethyl [3-(hydroxy)-5-methylbenzyl)thio]acetate

In the same manner as in Reference Example 24, ethyl{[3-(methoxymethoxy)-5-methylbenzyl]thio}acetate was obtained from[(3-(methoxymethoxy)-5-methylphenyl)methanol, and the obtained matterwas further processed by the method as described in Reference Example 25to obtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (3H, t), 2.29 (3H, s) 3.09 (2H,s), 3.73 (2H, s), 4.18 (2H, q), 4.79 (1H, s), 6.55 (1H, s), 6.62 (1H,s), 6.71 (1H, s).

Reference Example 80 Ethyl (3-hydroxy-5-methylphenyl)acetate

In the same manner as in Reference Example 59,[3-(methoxymethoxy))-5-methylphenyl]acetonitrile was obtained from[3-(methoxymethoxy)-5-methylphenyl]methanol, and the obtained matter wasfurther processed by the method as described in Reference Example 60 toobtain an objective product.

An oily matter; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.28 (3H, s), 3.51 (2H,s), 4.15 (2H, q), 4.88 (1H, s), 6.55-6.58 (2H, m), 6.65 (1H, s).

Reference Example 81 Ethyl(2E)-3-[2-ethyl-5-(3-methoxyphenyl)-3-furyl]acrylate

In the same manner as in Reference Example7,2-ethyl-5-(3-methoxyphenyl)-3-furaldehyde was obtained from[2-ethyl-5-(3-methoxyphenyl)-3-furyl]methanol obtained in ReferenceExample 6(13), and the obtained matter was further processed by themethod as described in Reference Example 8 to obtain an objectiveproduct.

An oily matter; ¹H-NMR (CDCl₃) δ 1.32 (3H, t), 1.33 (3H, t), 2.84 (2H,q), 3.86 (3H s), 4.25 (2H, q), 6.13 (1H, d), 6.73 (1H, s), 6.83 (1H,ddd), 7.18-7.35 (3H, m), 7.58 (1H, d).

Reference Example 82 Ethyl3-[2-ethyl-5-(3-methoxyphenyl)-3-furyl]propionate

In the same manner as in Reference Example 9, an objective product wasobtained from ethyl(2E)-3-[2-ethyl-5-(3-methoxyphenyl)-3-furyl]acrylate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 1.25 (3H, t) 2.49-2.75(6H, m), 3.85 (3H, s), 4.14 (2H, q), 6.46 (1H, s), 6.76 (1H, ddd),7.14-7.30 (3H, m).

Reference Example 83 3-[2-Ethyl-5-(3-methoxyphenyl)-3-furyl]propan-1-ol

In the same manner as in Reference Example 11, an objective product wasobtained from ethyl 3-[2-ethyl-5-(3-methoxyphenyl)-3-furyl]propionate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.75-1.89 (2H, m), 2.47(2H, t), 2.65 (2H, q), 3.69 (2H, q), 3.85 (3H, s), 6.48 (1H, S),6.73-6.79 (1H, m), 7.15-7.30 (3H, m).

Reference Example 84 1-[3-(Methoxymethoxy)phenyl]ethanol

To a solution of 3-(methoxymethoxy)benzaldehyde (13.3 g) intetrahydrofuran (100 ml) was added dropwise a 1 N solution (120 ml) ofmethylmagnesium bromide in tetrahydrofuran at −78° C. and the reactionsolution was stirred at −78° C. for 1 hour. The reaction solution waspoured into an aqueous ammonium chloride solution, and twice extractedwith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=6:1 to 2:1) to obtain an objectiveproduct (11.4 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.49 (3H, d), 1.79 (1H, d), 3.49 (3H, s) 4.82-4.93 (1H,m), 5.19 (2H, s), 6.92-7.06 (3H, m), 7.27 (1H, t).

Reference Example 85 S-{1-[3-(methoxymethoxy)phenyl]ethyl}thioacetate

In the same manner as in Reference Example 71, an objective product wasobtained from 1-[3-(methoxymethoxy)phenyl]ethanol.

An oily matter; ¹H-NMR (CDCl₃) δ 1.64 (3H, d), 2.30 (3H, s), 3.48 (3H,S), 4.71 (1H, q), 5.17 (2H, S), 6.90-7.00 (3H, m), 7.23 (1H, t).

Reference Example 86 Ethyl2-({1-[3-(methoxymethoxy)phenyl]ethyl}thio)-2-methylpropionate

In the same manner as in Reference Example 27, an objective product wasobtained from S-{1-[3-(methoxymethoxy)phenyl]ethyl}thioacetate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.20 (3H, t), 1.40 (3H, s) 1.52 (3H,S), 1.53 (3H, d), 3.48 (3H, S), 3.96 (1H, q), 3.97 (1H, q), 4.09 (1H,q), 5.17 (2H, s), 6.88 (1H, ddd), 6.97 (1H, d), 6.99 (1H, s), 7.20 (1H,t).

Reference Example 87 Ethyl2-{[1-(3-hydroxyphenyl)ethyl]thio}-2-methylpropionate

In the same manner as in Reference Example 28, an objective product wasobtained from ethyl2-({1-[3-(methoxymethoxy)phenyl)ethyl}thio)-2-methylpropionate. An oilymatter; ¹H-NMR (CDCl₃) δ 1.19 (3H, t), 1.40 (3H, s), 1.51 (3H, d), 1.52(3H, s), 3.92 (1H, q), 3.93 (1H, q), 4.06 (1H, q), 4.90 (1H, s), 6.67(1H, ddd), 6.82 (1H, t), 6.87 (1H, d), 7.14 (1H, t).

Reference Example 88 2-[3-(Methoxymethoxy)phenyl]propionitrile

To a solution of 1-[3-(methoxymethoxy)phenyl]ethanol (1.59 g), acetonecyanohydrin (1.1 g) and tributylphosphine (3.3 ml) in tetrahydrofuran(70 ml) was added 1,1′-(azodicarbonyl)dipiperidine (3.3 g) at roomtemperature and the mixture was stirred overnight. The solvent of thereaction solution was distilled off under reduced pressure anddiisopropyl ether was added. The precipitate was filtered off and washedwith diisopropyl ether. The solvent of the filtrate was distilled offunder reduced pressure and the obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=15:1 to 6:1) toobtain an objective product (0.88 g) as an oily matter.

An oily matter; ¹H-NMR (CDCl₃) δ 1.64 (3H, d), 3.49 (3H, s), 3.87 (1H,q), 5.19 (2H, s), 6.99-7.02 (3H, m), 7.30 (1H, t).

Reference Example 89 Ethyl 2-(3-hydroxyphenyl)propionate

In the same manner as in Reference Example 60, an objective product wasobtained from 2-[3-(methoxymethoxy)phenyl]propionitrile.

An oily matter; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 1.47 (3H, d), 3.65 (1H,q), 4.06-4.38 (2H, m), 4.88 (1H, s), 6.72 (1H, ddd), 6.79 (1H, dd), 6.85(1H, d), 7.17 (1H, t).

Reference Example 90 Ethyl2-(2-fluoro-4-methoxyphenoxy)-2-methylpropionate

To a solution of 2-fluoro-4-methoxyphenol (5.29 g) and ethyl2-bromo-2-methylpropionate (8.7 g) in N,N-dimethylformamide (30 ml) wasadded potassium carbonate (10.3 g) and the mixture was stirred at 90° C.overnight. The reaction solution was poured into water and twiceextracted with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=15:1) to obtain an objectiveproduct (5.86 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.31 (3H, t), 1.53 (6H, s), 3.75 (3H, s), 4.24 (2H, q),6.54 (1H, ddd), 6.63 (1H, dd), 6.98 (1H, t).

Reference Example 91 Ethyl2-(2-fluoro-4-hydroxyphenoxy)-2-methylpropionate

In the same manner as in Reference Example 57, an objective product wasobtained from ethyl 2-(2-fluoro-4-methoxyphenoxy)-2-methylpropionate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.31 (3H, t), 1.52 (6H, d) 4.24 (2H,q), 4.89 (1H, s), 6.46 (1H, ddd), 6.58 (1H, dd), 6.92 (1H, t).

Reference Example 92 Ethyl2-{[3-(methoxymethoxy)benzyl]oxy}-2-methylpropionate

To a solution of 3-(methoxymethoxy)benzylalcohol (8.26 g) andtriethylamine (10.6 ml) in ethyl acetate (100 ml) was added dropwise asolution of methanesulfonyl chloride (7.0 g) in ethyl acetate (30 ml)with ice-cooling and the mixture was stirred as such for 0.5 hour. Theproduced precipitate was filtered and washed with ethyl acetate. Thesolvent of the filtrate was distilled off under reduced pressure toobtain an oily matter.

To a solution of ethyl 2-hydroxyisobutyrate (13.4 g) in tetrahydrofuran(100 ml) was added a suspended matter (4.1 g) of 60% sodium hydride inliquid paraffin at room temperature and the mixture was stirred for 15minutes. A solution of the obtained oily matter in tetrahydrofuran (50ml) was added thereto at room temperature and the reaction mixture wasstirred at 65° C. for 3 days. The reaction solution was poured intowater and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1)to obtain an objective product (5.55 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.31 (3H, t), 1.51 (6H, s), 3.48 (3H, s), 4.22 (2H, q),4.44 (2H, s), 5.18 (2H, s), 6.92-6.97 (1H, m), 7.02-7.08 (2H, m), 7.25(1H, t).

Reference Example 93 Ethyl 2-[(3-hydroxybenzyl)oxy]-2-methylpropionate

In the same manner as in Reference Example 25, an objective product wasobtained from ethyl2-{[3-(methoxymethoxy)benzyl]oxy}-2-methylpropionate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 1.51 (6H, s), 4.22 (2H,q), 4.43 (2H, s), 4.86 (1H, s), 6.71-6.76 (1H, m), 6.90-6.93 (2H, m),7.19 (1H, t).

Reference Example 94 Methyl2-[(acetyloxy)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furoate

To a solution of methyl 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate(13.53 g) in ethyl acetate (300 ml) was added2,2′-azobis(isobutyronitrile) (0.39 g) and N-bromosuccinimide (8.48 g)and the mixture was heated under reflux for 2 hours. The solvent wasdistilled off under reduced pressure to obtain a mixture of a solidmatter and an oily matter. The obtained mixture was dissolved inN,N-dimethylformamide (100 ml) and sodium acetate (7.81 g) was added.The mixture was stirred at room temperature overnight. Water was addedand the mixture was diluted with ethyl acetate. The organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=5:1 to 2:1) to obtain an objective product (12.47g) as a solid matter.

Melting point 60-61° C.; ¹H-NMR (CDCl₃) δ 2.14 (3H, s), 3.89 (3H, s),5.46 (2H, s), 7.08 (1H, s), 7.66 (2H, d), 7.78 (2H, d).

Reference Example 95 Ethyl2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate

Methyl 2-[(acetyloxy)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furoate(5.0 g) was dissolved in a mixed solvent of tetrahydrofuran (60 ml) andmethanol (60 ml), and 1 N sodium hydroxide (32 ml) was added. Themixture was stirred at room temperature overnight. 1 N sodium hydroxide(20 ml) was further added thereto and then the mixture was stirred atroom temperature for 5 hours. The mixture was acidified withconcentrated hydrochloric acid and diluted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to obtain an oily matter. The obtained oily matter wasdissolved in N,N-dimethylformamide (50 ml). Sodium hydride (1.76 g) andethyl iodide (4.68 ml) were added with ice-cooling, and then the mixturewas stirred for 3 hours. 1 N hydrochloric acid was added and dilutedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and then dried over anhydrous magnesium sulfate. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1 to 5:1) to obtain an objective product (3.65 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.39 (3H, t), 3.63 (2H, q), 4.34 (2H, q),4.85 (2H, s), 7.04 (1H, s), 7.64 (2H, d), 7.78 (2H, d).

Reference Example 96{2-(Ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

In the same manner as in Reference Example 6, an objective product wasobtained from ethyl2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate obtained inReference Example 95.

Melting point 103-105° C.; ¹H-NMR (CDCl₃) δ 1.26 (3H, dt) 3.60 (2H, dq),4.57 (2H, s), 4.59 (2H, s), 6.77 (1H, s), 7.60 (2H, d), 7.73 (2H, d).

Reference Example 97 20 Ethyl 2-(4-hydroxy-2-methylbenzyl)butanoate

To a solution of ethyl 2-(diethoxyphosphoryl)butanoate (6.3 ml) intetrahydrofuran (50 ml) was added a suspended matter (1.33 g) of 60%sodium hydride in liquid paraffin with ice-cooling and the mixture wasstirred for 30 minutes.

A solution of 4-(benzyloxy)-2-methylbenzaldehyde (5.0 g) intetrahydrofuran (30 ml) was added thereto and the mixture was stirred atroom temperature overnight. 1 N hydrochloric acid was added to thereaction solution and the mixture was diluted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The obtained crude product was dissolved in ethanol(50 ml) and the atmosphere of the reaction vessel was substituted with anitrogen atmosphere. 10% palladium-carbon (1.0 g) was added and themixture was stirred overnight at room temperature under hydrogenatmosphere. A catalyst was filtered through Celite and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1to 2:1) to obtain an objective product (4.79 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.91 (3H, t), 1.19 (3H, t), 1.48-1.75 (2H, m), 2.25(3H, s), 2.47-2.72 (2H, m), 2.84 (1H, dd), 4.07 (2H, q), 4.83-5.05 (1H,br), 6.52-6.62 (2H, m), 6.94 (1H, d).

Reference Example 97(1) to Reference Example 97(2)

In the same manner as in Reference Example 97, the below-describedcompounds were obtained from phosphonate corresponding to4-(benzyloxy)-2-methylbenzaldehyde.

Reference Example 97(1) Ethyl3-(4-hydroxy-2-methylphenyl)-2-methylpropionate

An oily matter; ¹H-NMR (CDCl₃) δ 1.16 (3H, d), 1.19 (3H, t), 2.25 (3H,s), 2.53-2.72 (2H, m), 2.90-2.99 (1H, m), 4.19 (2H, q), 5.25 (1H, s),6.54-6.63 (2H, m), 6.94 (1H, d).

Reference Example 97(2) Ethyl3-(4-hydroxy-2-methylphenyl)-2-methoxypropionate

An oily matter; ¹H-NMR (CDCl₃) δ 1.32 (3H, t), 2.28 (3H, s), 2.95 (2H,d), 3.32 (3H, s), 3.86-3.93 (1H, m), 4.18 (2H, q), 5.10 (1H, s),6.56-6.64 (2H, m), 7.00 (1H, dd).

Reference Example 98 Ethyl 2-[(4-methoxyphenyl)thio]-2-methylpropionate

To a solution of 4-methoxybenzenethiol (3.7 ml) in N,N-dimethylformamide(100 ml) was added potassium carbonate (5.1 g) and ethyl2-bromoisobutyrate (5.96 g), and then the mixture was stirred at 50° C.overnight. After standing to cool, the mixture was diluted with ethylacetate and the organic layer was washed with water and saturated brine.Then, the organic layer was dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=30:1to 5:1) to obtain an objective product (7.11 g) as an oily matter.¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.45 (6H, s), 3.80 (3H, s), 4.10 (2H, q),6.84 (2H, d), 7.38 (2H, d).

Reference Example 99 Ethyl 2-[(4-hydroxyphenyl)thio]-2-methylpropionate

Aluminum chloride (0.88 g) was suspended in toluene (5 ml), octanethiol(3.5 ml) was added dropwise and the mixture was stirred until it wasuniform. A solution of ethyl2-[(4-methoxyphenyl)thio]-2-methylpropionate (7.06 g) in toluene (5 ml)was added and the mixture was stirred at room temperature for 3 hours.Water was added to the reaction mixture, and the mixture was dilutedwith ethyl acetate, washed with water and saturated brine and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1 to 5:1) and further byrecrystallization (hexane-diisopropyl ether) to obtain an objectiveproduct (6.23 g) as crystals.

Melting point 68-69° C.; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.47 (6H, s),4.14 (2H, q), 6.17 (1H, s), 6.68 (2H, d), 7.29 (2H, d).

Reference Example 100 Ethyl 3-(5-methoxy-1-benzofuran-2-yl)propionateEthyl 3-(5-methoxy-2,3-dihydro-1-benzofuran-2-yl)propionate

To a solution of ethyl (E)-3-(5-methoxy-1-benzofuran-2-yl)-2-propenoate(0.81 g) in ethyl acetate (10 ml) was added 10% palladium-carbon (0.20g) under nitrogen gas stream, and the mixture was stirred under hydrogenatmosphere at room temperature for 1 hour. A catalyst was filteredthrough Celite and the solvent was distilled off under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate 30:1 to 5:1) to obtain a mixture ofethyl 3-(5-methoxy-1-benzofuran-2-yl)propionate and ethyl3-(5-methoxy-2,3-dihydro-1-benzofuran-2-yl)propionate (0.80 g) as anoily matter.

¹H-NMR (CDCl₃) δ 1.25, 1.26 (3H, t), 1.98-2.09 (0.86H, m), 2.47-2.55(0.86H, m), 2.69-2.90 (1.58H, m), 3.08 (1.14H, t), 3.28 (0.42H, ddd),3.74 (1.26H, s), 3.82 (1.74H, s), 4.09-4.21 (2H, m), 4.70-4.85 (0.42H,m), 6.35 (0.58H, d), 6.63-6.64 (0.86H, m), 6.73-6.74 (0.42H, m), 6.80(0.58H, dd), 6.94 (0.58H, d), 7.27 (0.58H, d).

Reference Example 101 Ethyl 3-(5-hydroxy-1-benzofuran-2-yl)propionateEthyl 3-(5-hydroxy-2,3-dihydro-1-benzofuran-2-yl)propionate

Aluminum chloride (0.88 g) was suspended in toluene (5 ml) andoctanethiol (3.5 ml) was added dropwise. The mixture was stirred untilit was uniform. A mixture of ethyl3-(5-methoxy-1-benzofuran-2-yl)propionate and ethyl3-(5-methoxy-2,3-dihydro-1-benzofuran-2-yl)propionate (0.80 g) intoluene (5 ml) was added and the mixture was stirred at room temperaturefor 3 hours. Water was added to the reaction mixture, and the mixturewas diluted with ethyl acetate, washed with water and saturated brineand then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=30:1 to 2:1) to obtain amixture (0.56 g) of ethyl 3-(5-hydroxy-1-benzofuran-2-yl)propionate andethyl 3-(5-hydroxy-2,3-dihydro-1-benzofuran-2-yl)propionate as an oilymatter.

¹H-NMR (CDCl₃) δ 1.25, 1.26 (3H, t), 1.97-2.08 (0.84H, m), 2.47-2.55(0.84H, m), 2.70-2.85 (1.56H, m), 3.07 (1.16H, t), 3.24 (0.42H, dd),4.07-4.21 (2H, m), 4.69-4.83 (0.42H, m), 4.97 (0.42H, s), 5.23 (0.58H,s), 6.30 (0.58H, d), 6.57 (0.86H, s), 6.65-6.67 (0.42H, m), 6.72 (0.58H,dd), 6.88 (0.58H, d), 7.22 (0.58H, d).

Reference Example 102 Ethyl (5-methoxy-1-benzofuran-2-yl)acetate

To a solution of (5-methoxy-1-benzofuran-2-yl)methanol (2.40 g) intetrahydrofuran (100 ml) was sequentially added acetone cyanohydrin(1.85 ml), tributylphosphine (6.71 ml) and1,1′-(azodicarbonyl)dipiperidine (26.80 g) and the mixture was stirredat 0° C. for 2 hours and at room temperature for 2 hours. The solvent ofthe reaction solution was distilled off under reduced pressure anddiisopropyl ether was added. The precipitate was filtered off and washedwith diisopropyl ether. The solvent of the filtrate was distilled offunder reduced pressure of filtrate, and the obtained crude product wassubject to silica gel column chromatography (hexane:ethyl acetate=30:1to 10:1) to obtain an oily matter. The obtained oily matter wasdissolved in ethanol (10 ml). An 8 N aqueous sodium hydroxide solution(10 ml) was added, and the mixture was heated under reflux overnight.The mixture was diluted with water and the aqueous layer was washed withether. Then, the mixture was acidified with concentrated hydrochloricacid and extracted with ethyl acetate. The organic layer was combined,washed with water and saturated brine and then dried over anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure to obtain a crude product. The crude product was dissolved inethanol (10 ml) and concentrated sulfuric acid (0.1 ml) was added. Themixture was heated under reflux overnight. After standing to cool, themixture was diluted with ethyl acetate and the organic layer was washedwith water, a saturated sodium bicarbonate solution and saturated brineand then dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 5:1) to obtain an objective product (0.46 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.28 (3H, t), 3.79 (2H, s), 3.82 (3H, s), 4.20 (2H, q),6.55-6.56 (1H, m), 6.83 (1H, dd), 6.97 (1H, d), 7.31 (1H, dd).

Reference Example 103 Ethyl (5-hydroxy-1-benzofuran-2-yl)acetate

Aluminum chloride (0.53 g) was suspended in toluene (4 ml) andoctanethiol (1.65 ml) was added dropwise. The mixture was stirred untilit was uniform. A solution of ethyl (5-methoxy-1-benzofuran-2-yl)acetate(0.37 g) in toluene (4 ml)

was added, and then the mixture was stirred at room temperature for 3hours. Water was added to the reaction mixture, and the mixture wasdiluted with ethyl acetate, washed with water and saturated brine andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=20:1 to 5:1) to obtain anobjective product (0.29 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.28 (3H, t), 3.78 (2H, s), 4.21 (2H, q), 5.10 (1H, s),6.48 (1H, d), 6.73 (1H, dd), 6.88 (1H, d), 7.24 (1H, d).

Reference Example 104 2-Formyl-5-methoxyphenyl trifluoromethanesulfonate

2-Hydroxy-4-methoxybenzaldehyde (10.0 g) was dissolved intetrahydrofuran (200 ml), pyridine (39 ml) and trifluoromethanesulfonicanhydride (12.2 ml) were sequentially added with ice-cooling, and themixture was stirred at room temperature overnight. A saturated sodiumbicarbonate solution was added, and then the mixture was diluted withethyl acetate, washed with 1 N hydrochloric acid, water and saturatedbrine, and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=20:1 to 5:1) to obtainan objective product (13.07 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.92 (3H, s), 6.87 (1H, d), 7.03 (1H, dd), 7.94 (1H,d), 10.12 (1H, s).

Reference Example 105 Ethyl(E)-3-(4-methoxy-2{([(trifluoromethyl)sulfonyl]oxy}phenyl)-2-propenoate

To a solution of ethyl diethylphosphonoacetate (6.1 ml) intetrahydrofuran (100 ml) was added a suspended matter (2.2 g) of 60%sodium hydride in liquid paraffin with ice-cooling and then the mixturewas stirred for 0.5 hour. A solution of 2-formyl-5-methoxyphenyltrifluoromethanesulfonate (10.0 g) in tetrahydrofuran (50 ml), and thenthe mixture was stirred at 0° C. for 2 hours. 1 N hydrochloric acid wasadded to the reaction solution and then diluted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=20:1 to 10:1) toobtain an objective product (9.07 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.33 (3H, t), 3.86 (3H, s), 4.27 (2H, q), 6.38 (1H, d),6.86 (1H, d), 6.95 (1H, dd), 7.63 (1H, d), 7.80 (1H, d).

Reference Example 106 Ethyl (E)-3-(2-allyl-4-methoxyphenyl)-2-propenoate

A solution of ethyl(E)-3-(4-methoxy-2-{[(trifluoromethyl)sulfonyl]oxy}phenyl)-2-propenoate(8.92 g) in N,N-dimethylformamide (100 ml) was added allyltributyl tin(9.2 ml) and tetrakis(triphenylphosphine) palladium (1.46 g) undernitrogen atmosphere, and the mixture was stirred at 80° C. overnight.The mixture was diluted with ethyl acetate, washed with a saturatedsodium bicarbonate solution, water and saturated brine and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=30:1 to 20:1 to 10:1) toobtain an objective product (5.84 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.32 (3H, t), 3.50 (2H, d), 3.81 (3H, s), 4.24 (2H, q),4.98-5.11 (2H, m), 5.87-6.00 (1H, m), 6.25 (1H, d), 6.73-6.79 (2H, m),7.55 (1H, d), 7.91 (1H, d).

Reference Example 107 Ethyl 3-(4-methoxy-2-propylphenyl)propionate

To a solution of ethyl (E)-3-(2-allyl-4-methoxyphenyl)-2-propenoate(5.23 g) in ethyl acetate (50 ml) was added 10% palladium-carbon (1.0 g)and the mixture was stirred at room temperature overnight. A catalystwas filtered and the solvent was distilled off under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=30:1 to 5:1) to obtain an objectiveproduct (5.35 g) as an oily matter. ¹H-NMR (CDCl₃) δ 0.98 (3H, t), 1.25(3H, t), 1.57-1.65 (2H, m), 2.51-2.58 (4H, m), 2.86-2.91 (2H, m), 3.77(3H, m), 4.13 (2H, q), 6.65-6.70 (2H, m), 7.04 (1H, d).

Reference Example 108 Ethyl 3-(4-hydroxy-2-propylphenyl)propionate

Aluminum chloride (4.02 g) was suspended in toluene (30 ml) andoctanethiol (13 ml) was added dropwise. The mixture was stirred until itwas uniform. Then, a solution of ethyl3-(4-methoxy-2-propylphenyl)propionate (3.02 g) in toluene (10 ml) wasadded thereto and the mixture was stirred at room temperature for 3hours. Water was added to the reaction mixture, and the mixture wasdiluted with ethyl acetate, washed with water and saturated brine andthen dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=20:1 to 2:1) to obtain anobjective product (2.52 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.97 (3H, t), 1.24 (3H, t), 1.52-1.65 (2H, m),2.50-2.56 (4H, m), 2.85-2.90 (2H, m), 4.13 (2H, q), 6.59 (1H, dd), 6.63(1H, d), 6.97 (1H, d).

Reference Example 109 Ethyl2-(2-chloro-4-methoxyphenoxy)-2-methylpropionate

To a solution of 4-methoxy-2-chlorophenol (2.0 g) inN,N-dimethylformamide (10 ml) was added ethyl 2-bromoisobutyrate (2.0ml) and a suspended matter (0.66 g) of 60% sodium hydride in liquidparaffin was added to the mixture with ice-cooling. The mixture wasstirred at room temperature overnight. A suspended matter (0.30 g) of60% sodium hydride in liquid paraffin was added thereto and the mixturewas stirred at room temperature for 5 hours. Water was added theretowith ice-cooling and then the mixture was diluted with ethyl acetate.The organic layer was washed with water and saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=5:1) to obtain an objectiveproduct (1.01 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.31 (3H, t), 1.56 (6H, s), 3.76 (3H, s), 4.26 (2H, q),6.68 (1H, dd), 6.92 (1H, d), 6.95 (1H, d).

Reference Example 110 Ethyl2-(2-chloro-4-hydroxyphenoxy)-2-methylpropionate

In the same manner as in Reference Example 108, an objective product wasobtained from ethyl 2-(2-chloro-4-methoxyphenoxy)-2-methylpropionateobtained in Reference Example 109.

An oily matter; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 1.56 (6H, s) 4.26 (2H,q), 4.84 (1H, s), 6.61 (1H, dd), 6.88 (1H, d), 6.90 (1H, d).

Reference Example 111S-[4-fluoro-3-(methoxymethoxy)benzyl]ethylthioacetate

To a solution of [4-fluoro-3-(methoxymethoxy)phenyl]methanol (5.28 g) inethyl acetate (60 ml) was added dropwise triethylamine (4.8 ml) andmethanesulphonyl chloride (2.31 ml) with ice-cooling, and the mixturewas stirred for 30 minutes. Insolubles were filtered through Celite andthe solvent was distilled off under reduced pressure to obtain an oilymatter. The obtained oily matter was dissolved in N,N-dimethylformamide(100 ml) and potassium thioacetate (3.90 g) was added. The reactionmixture was stirred at room temperature for 2 hours. The mixture wasdiluted with ethyl acetate, was washed with water and saturated brineand then dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtainan objective product (5.60 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.34 (3H, s), 3.52 (3H, s), 4.05 (2H, s), 5.19 (2H, s),6.85-7.04 (2H, m), 7.12 (1H, dd).

Reference Example 112 Ethyl2-{[4-fluoro-3-(methoxymethoxy)benzyl]thio}-2-methylpropionate

To a solution of S-[4-fluoro-3-(methoxymethoxy)benzyl]ethanethioate(2.50 g) in ethanol (20 ml) was added 1 N sodium hydroxide (11 ml) andthe mixture was stirred at room temperature overnight. The mixture wasacidified with 1 N hydrochloric acid and diluted with ethyl acetate.Then, the mixture was washed with water and saturated brine and driedover anhydrous magnesium sulfate and the solvent was distilled off underreduced pressure to obtain an oily matter. The obtained oily matter wasdissolved in N,N-dimethylformamide (30 ml) and potassium carbonate (2.11g) and ethyl 2-bromoisobutyrate (1.80 ml) were added. The mixture wasstirred at room temperature overnight. The mixture was diluted withethyl acetate and then washed with water and saturated brine. Themixture was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain an oily matter. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=30:1 to 10:1) to obtain an objective product (1.95 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.52 (6H, s), 3.51 (3H, s), 3.78 (2H, s),4.13 (2H, q), 5.20 (2H, s), 6.86-7.04 (2H, m), 7.12 (1H, dd).

Reference Example 113 Ethyl2-[(4-fluoro-3-(hydroxybenzyl)thio]-2-methylpropionate

To a solution of ethyl2-{[4-fluoro-3-(methoxymethoxy)benzyl]thio}-2-methylpropionate (1.0 g)in ethanol (10 ml) was added concentrated hydrochloric acid (0.5 ml) andthe mixture was stirred at 50 to 60° C. for 1 hour. The mixture wasdiluted with ethyl acetate and then washed with water and saturatedbrine. The mixture was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1 to 2:1) to obtain an objective product (0.86g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.53 (6H, s), 3.75 (2H, s), 4.13 (2H, q),5.25 (1H, br), 6.74-6.79 (1H, m), 6.93-7.00 (2H, m).

Reference Example 114 S-(2-Fluoro-5-methoxybenzyl)ethanethioate

In the same manner as in Reference Example 111, an objective product wasobtained from (2-fluoro-5-methoxybenzyl)methanol obtained in ReferenceExample 55. An oily matter; ¹H-NMR (CDCl₃) δ 2.35 (3H, s), 3.76 (3H, s),4.11 (2H, s), 6.68-6.76 (1H, m), 6.85-6.98 (2H, m).

Reference Example 115 Ethyl2-[(2-fluoro-5-methoxybenzyl)thio]-2-methylpropionate

In the same manner as in Reference Example 112, an objective product wasobtained S-(2-fluoro-5-methoxybenzyl)ethanethioate obtained in ReferenceExample 114.

An oily matter; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.55 (6H, s) 3.76 (3H,s), 3.84 (2H, s), 4.11 (2H, q), 6.67-6.77 (1H, m), 6.85 (1H, dd), 6.92(1H, t).

Reference Example 116 Ethyl2-[(2-fluoro-5-hydroxybenzyl)thio]-2-methylpropionate

In the same manner as in Reference Example 108, an objective product wasobtained from ethyl2-[(2-fluoro-5-methoxybenzyl)thio]-2-methylpropionate obtained inReference Example 115.

An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 1.55 (6H, s) 3.81 (2H,s), 4.10 (2H, q), 5.40 (1H, s), 6.64-6.69 (1H, m), 6.80-6.93 (2H, m).

Reference Example 117 (2-Fluoro-3-methoxyphenyl)methanol

In the same manner as in Reference Example 6, an objective product wasobtained from 2-fluoro-3-methoxybenzoic acid.

Melting point 59-60° C.; ¹H-NMR (CDCl₃) δ 1.87 (1H, t), 3.88 (3H, s),4.75 (2H, d), 6.88-7.09 (3H, m).

Reference Example 118 S-(2-fluoro-3-methoxybenzyl)ethanethioate

In the same manner as in Reference Example 111, an objective product wasobtained from (2-fluoro-3-methoxyphenyl)methanol obtained in ReferenceExample 117. An oily matter; ¹H-NMR (CDCl₃) δ 2.38 (3H, s), 3.86 (3H,s), 4.16 (2H, d), 6.82-7.01 (3H, m).

Reference Example 119 Ethyl2-[(2-fluoro-3-methoxybenzyl)thio]-2-methylpropionate

In the same manner as in Reference Example 112, an objective product wasobtained from S-(2-fluoro-3-methoxybenzyl)ethanethioate obtained inReference Example 118.

An oily matter; ¹H-NMR (CDCl₃) δ 1.28 (3H, t), 1.55 (6H, s), 3.86 (2H,s), 3.88 (3H, s), 4.14 (2H, q), 6.81-7.02 (3H, m).

Reference Example 120 Ethyl2-[(2-fluoro-3-hydroxyphenyl)thio]-2-methylpropionate

In the same manner as in Reference Example 108, an objective product wasobtained from ethyl2-[(2-fluoro-3-methoxybenzyl)thio]-2-methylpropionate obtained inReference Example 119.

An oily matter; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.55 (6H, s), 3.86 (2H,s), 4.13 (2H, q), 5.29 (1H, d), 6.80-6.99 (3H, m).

Reference Example 121 (2-Fluoro-3-methoxyphenyl)acetonitrile

In the same manner as in Reference Example 88, an objective product wasobtained from (2-fluoro-3-methoxyphenyl)methanol obtained in ReferenceExample 117. An oily matter; ¹H-NMR (CDCl₃) δ 3.76 (2H, s), 3.89 (3H,s), 6.91-7.15 (3H, m).

Reference Example 122 Ethyl (2-fluoro-3-methoxyphenyl)acetate

A mixture of (2-fluoro-3-methoxyphenyl)acetonitrile (0.77 g), 8 N sodiumhydroxide (10 ml) and ethanol (10 ml) was heated under reflux overnight.The solvent of the reaction solution was distilled off under reducedpressure, and the reaction solution was acidified with concentratedhydrochloric acid and twice extracted with ethyl acetate. The collectedorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain an oily matter. The obtained oily matter was dissolved inethanol (10 ml), concentrated sulfuric acid (0.1 ml) was added, and thenthe mixture was heated under reflux overnight. The reaction solution wasdiluted with ethyl acetate and washed with water, a saturated sodiumbicarbonate solution and saturated brine. The organic layer was driedover anhydrous sodium sulfate and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:1) to obtain an objectiveproduct (0.79 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.25 (3H, t), 3.65 (3H, s), 3.87 (2H, s) 4.16 (2H, q),6.79-6.90 (2H, m), 6.98-7.04 (1H, m).

Reference Example 123 Ethyl (2-fluoro-3-hydroxyphenyl)acetate

In the same manner as in Reference Example 108, an objective product wasobtained from ethyl (2-fluoro-3-methoxyphenyl)acetate obtained inReference Example 122. An oily matter; ¹H-NMR (CDCl₃) δ 1.26 (3H, t),3.65 (2H, s), 4.17 (2H, q), 5.51 (1H, s), 6.73-6.86 (1H, m), 6.88-6.98(2H, m).

Reference Example 124 Methoxymethyl 4-chloro-3-(methoxymethoxy)benzoate

To a solution of 4-chloro-3-hydroxybenzoic acid (3.11 g) intetrahydrofuran (50 ml) was added N-ethyldiisopropylamine (9.4 ml) andchloromethylmethyl ether (3.5 ml) and the mixture was heated underreflux overnight. The mixture was diluted with ethyl acetate and thenwashed with water and saturated brine. The mixture was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain an oily matter. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=30:1 to 5:1) toobtain an objective product (4.39 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.53 (3H, s), 3.54 (3H, s), 5.31 (2H, s), 5.47 (2H, s),7.45 (1H, d), 7.68 (1H, dd), 7.84 (1H, d).

Reference Example 125 [4-Chloro-3-(methoxymethoxy)phenyl]methanol

In the same manner as in Reference Example 6, an objective product wasobtained from methoxymethyl 4-chloro-3-(methoxymethoxy)benzoate obtainedin Reference Example 124. An oily matter; ¹H-NMR (CDCl₃) δ 3.52 (3H, s),4.64 (2H, d) 5.25 (2H, s), 6.91-6.96 (1H, m), 7.17 (1H, d), 7.34 (1H,d).

Reference Example 126 Methyl (4-chloro-3-hydroxyphenyl)acetate

To a solution of [4-chloro-3-(methoxymethoxy)phenyl]methanol (2.01 g),acetone cyanohydrin (1.4 ml) and tributylphosphine (5.0 ml) intetrahydrofuran (100 ml) was added 1,1′-(azodicarbonyl)dipiperidine(5.05 g) at room temperature, and the mixture was stirred overnight. Thesolvent of the reaction solution was distilled off under reducedpressure and diisopropyl ether was added. The precipitate was filteredoff and washed with diisopropyl ether. The solvent of the filtrate wasdistilled off under reduced pressure and the obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=30:1to 5:1) to obtain an oily matter. The obtained oily matter was dissolvedin ethanol (10 ml) and 8 N sodium hydroxide (5 ml) was added. Themixture was heated under reflux overnight. The solvent of the reactionsolution was distilled off under reduced pressure. The reaction solutionwas acidified with concentrated hydrochloric acid and twice extractedwith ethyl acetate. The collected organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The obtained oily matter was dissolved in 10% hydrochloricacid-methanol (10 ml) and the mixture was stirred at room temperatureovernight. The solvent was distilled off under reduced pressure andpurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 5:1) to obtain an objective product (0.55 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.56 (2H, s), 3.69 (3H, s), 5.68 (1H, s), 6.79 (1H,dd), 6.94 (1H, d), 7.25 (1H, d).

Reference Example 127 S-[4-chloro-3-(methoxymethoxy)benzyl]ethanethioate

In the same manner as in Reference Example 111, an objective product wasobtained from [4-chloro-3-(methoxymethoxy)phenyl]methanol obtained inReference Example 125.

An oily matter; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 3.52 (3H, s), 4.05 (2H,s), 5.23 (2H, s), 6.88 (1H, dd), 7.09 (1H, d), 7.27 (1H, d).

Reference Example 128 Ethyl2-[(4-chloro-3-hydroxybenzyl)thio]-2-methylpropionate

To a solution of S-[4-chloro-3-(methoxymethoxy)benzyl]ethanethioate(1.72 g) in ethanol-tetrahydrofuran (10 ml-10 ml) was added 1 N sodiumhydroxide (10 ml) and the mixture was stirred at room temperature for 3days. The mixture was acidified with 1 N hydrochloric acid, diluted withethyl acetate and then washed with water and saturated brine. Themixture was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain an oily matter. Theobtained oily matter was dissolved in N,N-dimethylformamide (30 ml).Potassium carbonate (1.37 g) and ethyl 2-bromoisobutyrate (1.2 ml) wereadded and the mixture was stirred at 50° C. overnight. The mixture wasdiluted with ethyl acetate and then washed with water and saturatedbrine. The mixture was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=30:1 to 10:1) to obtain an oily matter. Theobtained oily matter was dissolved in ethanol (10 ml) and concentratedhydrochloric acid (0.1 ml) was added. The mixture was stirred at 60° C.overnight. The solvent was distilled off under reduced pressure. Theresultant was diluted with ethyl acetate, washed with water andsaturated brine and then dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 5:1) to obtain an objective product (0.45 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.52 (6H, s), 3.76 (2H, s) 4.12 (2H, q),5.58 (1H, s), 6.82 (1H, dd), 6.98 (1H, d), 7.22 (1H, d).

Reference Example 129 Ethyl (3-hydroxy-1H-indazol-1-yl)acetate

To a solution of 3-indazolinone (5.0 g) in N,N-dimethylformamide (150ml) was added to potassium carbonate (5.14 g) and ethyl bromoacetate(4.13 ml) and the mixture was stirred at room temperature overnight. Themixture was diluted with ethyl acetate and then washed with water andsaturated brine. The mixture was dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure to obtain anoily matter. The residue was purified by recrystallization (hexane-ethylacetate) to obtain an objective product (1.47 g) as crystals.

Melting point 181-182° C.; ¹H-NMR (CDCl₃) δ 1.25 (3H, t) 4.22 (2H, q),4.84 (2H, s), 7.09-7.20 (2H, m), 7.41-7.49 (1H, m), 7.77 (1H, d).

Reference Example 130 5-(Methoxymethoxy)-2-nitrobenzaldehyde

To a solution of 5-hydroxy-2-nitrobenzaldehyde (25 g) inN,N-dimethylformamide (300 ml) was added chloromethylmethyl ether (13.7ml) and a suspended matter (7.2 g) of 60% sodium hydride in liquidparaffin was added to the mixture with ice-cooling. The mixture wasstirred at room temperature overnight. 1 N hydrochloric acid was addeddropwise with ice-cooling, and the mixture was diluted with ethylacetate and then washed with water and saturated brine. The mixture wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain crude crystals. The residue waspurified by recrystallization (hexane-ethyl acetate) to obtain anobjective product (23.37 g) as crystals.

Melting point 68-69° C.; ¹H-NMR (CDCl₃) δ 3.49 (3H, s), 5.29 (2H, s),7.29 (1H, dd), 7.46 (1H, d), 8.15 (1H, d), 10.45 (1H, 5).

Reference Example 131 Ethyl5-(methoxymethoxy)-1-benzothiophene-2-carboxylate

To a solution of 5-(methoxymethoxy)-2-nitrobenzaldehyde (20 g) inN,N-dimethylformamide (300 ml) was added ethyl thioglycollate (12.5 ml)and potassium carbonate (16.36 g) and the mixture was stirred at 60° C.overnight. Water was added thereto and the mixture was extracted withethyl acetate. The combined organic layer was washed with water andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain an oily matter. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=30:1 to 5:1) to obtain an objectiveproduct (6.60 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.40 (3H, t), 3.50 (3H, s), 4.39 (2H, q), 5.22 (2H, s),7.18 (1H, dd), 7.49 (1H, d), 7.72 (1H, d), 7.95 (1H, s).

Reference Example 132 [5-(Methoxymethoxy)-1-benzothien-2-yl]methanol

In the same manner as in Reference Example 6, an objective product wasobtained from ethyl 5-(methoxymethoxy)-1-benzothiophen-2-carboxylateobtained in Reference Example 131.

Melting point 74-75° C.; ¹H-NMR (CDCl₃) δ 2.03 (1H, t), 3.50 (3H, s),4.89 (2H, d), 5.21 (2H, s), 7.05 (1H, dd), 7.12 (1H, d), 7.38 (1H, d),7.67 (1H, d)

Reference Example 133 [5-(Methoxymethoxy)-1-benzothien-2-yl]acetonitrile

In the same manner as in Reference Example 88, an objective product wasobtained from [5-(methoxymethoxy)-1-benzothien-2-yl]methanol obtained inReference Example 132. An oily matter; ¹H-NMR (CDCl₃) δ 3.51 (3H, s),3.97 (2H, d) 5.22 (2H, s), 7.08 (1H, dd), 7.23 (1H, s), 7.40 (1H, d),7.65 (1H, d).

Reference Example 134 Methyl (5-hydroxy-1-benzothien-2-yl)acetate

[5-(Methoxymethoxy)-1-benzothien-2-yl]acetonitrile (1.03 g) wasdissolved in ethanol (10 ml) and 8 N sodium hydroxide (10 ml) was added.The mixture was heated under reflux overnight. The solvent of thereaction solution was distilled off under reduced pressure, and thereaction solution was acidified with concentrated hydrochloric acid andthen extracted with ethyl acetate twice. The collected organic layer waswashed with saturated brine and then dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure toobtain an oily matter. The obtained oily matter was dissolved in 10%hydrochloric acid-methanol (10 ml) and the mixture was stirred at roomtemperature overnight. The solvent was distilled off under reducedpressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain an objectiveproduct (0.43 g) as an oily matter.

Melting point 136-137° C.; ¹H-NMR (CDCl₃) δ 3.75 (3H, s), 3.89 (2H, s),5.09 (1H, s), 6.86 (1H, dd), 7.03 (1H, s), 7.10 (1H, d), 7.59 (1H, d).

Reference Example 135 5-(Methoxymethoxy)-1-benzothiophene-2-carbaldehyde

In the same manner as in Reference Example 7, an objective product wasobtained from [5-(methoxymethoxy)-1-benzothien-2-yl]methanol obtained inReference Example 132. ¹H-NMR (CDCl₃) δ 3.51 (3H, s), 5.25 (2H, s), 7.25(1H, dd), 7.58 (1H, d), 7.78 (1H, d), 7.94 (1H, s), 10.07 (1H, s).

Reference Example 136 Ethyl(E)-3-[5-(methoxymethoxy)-1-benzothien-2-yl]-2-propenoate

In the same manner as in Reference Example 8, an objective product wasobtained from 5-(methoxymethoxy)-1-benzothiophene-2-carbaldehydeobtained in Reference Example 135.

Melting point 81-82° C.; ¹H-NMR (CDCl₃) δ 1.34 (3H, t), 3.50 (3H, s),4.27 (2H, q), 5.22 (2H, s), 6.27 (1H, d), 7.11 (1H, dd), 7.37 (1H, s),7.41 (1H, d), 7.66 (1H, d), 7.84 (1H, d).

Reference Example 137 Ethyl3-[5-(methoxymethoxy)-1-benzothien-2-yl]propionate

To a solution of ethyl(E)-3-[5-(methoxymethoxy)-1-benzothien-2-yl]-2-propenoate (1.46 g) inethyl acetate (20 ml) was added 10% palladium-carbon (1.0 g) and themixture was stirred under hydrogen atmosphere at room temperatureovernight. A catalyst was filtered through Celite and the filtrate wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 5:1) to obtain an objective product (1.20 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.25 (3H, t), 2.73 (2H, t), 3.21 (2H, t), 3.50 (3H, s),4.16 (2H, q), 5.20 (2H, s), 6.96 (1H, s), 7.00 (1H, dd), 7.33 (1H, d),7.62 (1H, d).

Reference Example 138 Ethyl 3-(5-hydroxy-1-benzothien-2-yl)propionate

Ethyl 3-[5-(methoxymethoxy)-1-benzothien-2-yl]propionate (1.20 g) wasdiluted with ethanol (20 ml) and concentrated hydrochloric acid (1 ml)was added. The mixture was stirred at 60° C. for 3 hours. The solventwas distilled off under reduced pressure and the mixture was dilutedwith ethyl acetate, washed with water and saturated brine and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to obtain an oily matter. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) toobtain an objective product (0.87 g) as crystals. Melting point 111-113°C.; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 2.73 (2H, t), 3.20 (2H, t), 4.16 (2H,q), 5.19 (1H, s), 6.82 (1H, dd), 6.89 (1H, s), 7.06 (1H, d), 7.56 (1H,d).

Reference Example 139(E)-4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-buten-1-ol

To a suspension of (3-hydroxypropyl)triphenylphosphonium bromide (12.41g) in tetrahydrofuran (60 ml) was added dropwise n-butyllithium (a 1.6 Mhexane solution, 36 ml) with ice-cooling and the mixture was stirred for30 minutes. Then, a solution of2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (6.41 g) intetrahydrofuran (50 ml) was added dropwise and the mixture was stirredfor 1.5 hours with ice-cooling. 1 N hydrochloric acid was added and themixture was diluted with ethyl acetate. The organic layer was washedwith water and saturated brine and then dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure toobtain an oily matter. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1 to 1:1) to obtain an objectiveproduct (4.77 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.37 (3H, s), 2.47 (2H, q), 3.75 (2H, t), 5.90 (1H,dt), 6.30 (1H, d), 6.82 (1H, s), 7.60 (2H, d), 7.70 (2H, d).

Reference Example 1404-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-1-butanol

In the same manner as in Reference Example 9, an objective product wasobtained from(E)-4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-buten-1-olobtained in Reference Example 139.

An oily matter; ¹H-NMR (CDCl₃) δ 1.59-1.65 (5H, m), 2.29 (3H, s),2.36-2.43 (2H, m), 3.64-3.70 (2H, m), 6.58 (1H, s), 7.57 (2H, d), 7.67(2H, d).

Reference Example 141S-{[5-(methoxymethoxy)-1-benzothien-2-yl]methyl}ethanethioate

In the same manner as in Reference Example 111, an objective product wasobtained from [5-(methoxymethoxy)-1-benzothien-2-yl]methanol obtained inReference Example 132. An oily matter; ¹H-NMR (CDCl₃) δ 2.37 (3H, s),3.49 (3H, s) 4.35 (2H, s), 5.20 (2H, s), 7.02 (1H, dd), 7.11 (1H, d),7.34 (1H, d), 7.60-7.63 (1H, m).

Reference Example 142 Ethyl2-({[5-(methoxymethoxy)-1-benzothien-2-yl)methyl}thio)-2-methylpropionate

In the same manner as in Reference Example 112, an objective product wasobtained fromS-{[5-(methoxymethoxy)-1-benzothien-2-yl]methyl}ethanethioate obtainedin Reference Example 141.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.55 (6H, s), 3.49 (3H, s), 4.10 (2H, s),4.11 (2H, q), 5.20 (2H, s), 7.00 (1H, dd), 7.08 (1H, s), 7.32 (1H, d),7.60 (1H, d).

Reference Example 143 Ethyl2-{[(5-hydroxy-1-benzothien-2-yl)methyl]thio}-2-methylpropionate

In the same manner as in Reference Example 138, an objective product wasobtained from ethyl2-({[5-(methoxymethoxy)-1-benzothien-2-yl)methyl}thio)-2-methylpropionateobtained in Reference Example 142.

An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 1.56 (6H, s), 4.05-4.16(4H, m), 4.93 (1H, s), 6.85 (1H, dd), 7.04 (1H, d), 7.08 (1H, d), 7.57(1H, d).

Reference Example 144tert-Butyl(dimethyl)[(2-methyl-3-furyl)methoxy]silane

To a suspension of aluminum lithium hydride (9.2 g) in tetrahydrofuran(200 ml) was added dropwise a solution of ethyl 2-methyl-3-furoate (31.1g) in tetrahydrofuran (100 ml) with ice-cooling and the mixture wasstirred at 0° C. for 1 hour. The reaction solution was ice-cooled andwater (9 ml), a 15% aqueous sodium hydroxide solution (9 ml) and water(23 ml) were sequentially added dropwise thereto. Excess aluminumlithium hydride was decomposed and then the resulting mixture wasstirred as such at room temperature for 2 hours. The obtainedprecipitate was filtered off and washed with ethyl acetate. The solventof the collected filtrate was distilled off under reduced pressure toobtain an oily matter.

To a solution of the obtained oily matter, 4-N,N-dimethylaminopyridine(1.2 g) and triethylamine (33.8 ml) in tetrahydrofuran (250 ml) wasadded tert-butyl chlorodimethylsilane (33.5 g) at room temperature andthe mixture was stirred as such overnight. The reaction solution waspoured into water and twice extracted with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=15:1) to obtain an objective product (38.2 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.08 (6H, s), 0.91 (9H, s), 2.26 (3H, s), 4.51 (2H, s),6.31 (1H, d), 7.22 (1H, d).

Reference Example 145 tert-Butyl{[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-3-furyl]methoxy}dimethylsilane

To a solution of 2,2,6,6-tetramethylpiperidine (27.9 ml) intetrahydrofuran (150 ml) was added dropwise a 1.6 N solution (100 ml) ofn-butyllithium in hexane with ice-cooling and the mixture was stirredfor 10 minutes. The reaction mixture was cooled to −78° C., and thentriisopropyl borate (40.2 g) andtert-butyl(dimethyl)[(2-methyl-3-furyl)methoxy]silane (24.2 g) wasadded. After the mixture was stirred at −78° C. for 2 hours, thetemperature was slowly elevated to room temperature over 4 hours, andthen the mixture was stirred at room temperature overnight. The reactionsolution was poured into an aqueous ammonium chloride solution and 3times extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain an oily matter.

A solution of the obtained oily matter and 2,2-dimethyl-1,3-propanediol(13.3 g) in toluene (200 ml) was stirred at room temperature overnight.The reaction solution was washed with water and the aqueous layerextracted with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=30:1 to 9:1) to obtain anobjective product (12.9 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.07 (6H, s), 0.90 (9H, s), 1.01 (6H, s), 2.31 (3H, s),3.74 (4H, s), 4.50 (2H, s), 6.91 (1H, s).

Reference Example 146 [5-(4-Methoxyphenyl)-2-methyl-3-furyl]methanol

To a solution of tert-butyl{[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-3-furyl]methoxy}dimethylsilane(4.06 g) in a mixed solvent of toluene-water (30 ml-30 ml) was addedsodium carbonate (2.54 g) and 4-bromoanisole (1.8 ml) and the atmosphereof the reaction vessel was substituted with a nitrogen atmosphere. Then,tetrakis(triphenylphosphine) palladium (0.70 g) was added thereto andthe mixture was stirred at 80° C. overnight. The mixture was dilutedwith ethyl acetate and the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=40:1 to 10:1) to obtain an oily matter. Theobtained oily matter was dissolved in tetrahydrofuran (20 ml) andtetra-n-butylammonium fluoride (a 1 M tetrahydrofuran solution, 15 ml)was added dropwise thereto and the mixture was stirred at roomtemperature for 1 hour. The mixture was diluted with ethyl acetate andthe organic layer was washed with water and saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain an oily matter. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1to 1:1) to obtain an objective product (0.78 g) as crystals.

Melting point 62-64° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 3.82 (3H, s),4.49 (2H, s), 6.49 (1H, s), 6.90 (2H, d), 7.55 (2H, d).

Reference Example 146(1) to Reference Example 146(4)

In the same manner as in Reference Example 146, the below-describedcompounds were obtained from aryl halide corresponding to tert-butyl{[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-3-furyl]methoxy}dimethylsilaneobtained in Reference Example 145.

Reference Example 146(1) [5-(3-Fluorophenyl)-2-methyl-3-furyl]methanol

An oily matter; ¹H-NMR (CDCl₃) δ 2.36 (3H, s), 4.50 (2H, s), 6.65 (1H,s), 6.85-6.96 (1H, m), 7.25-7.40 (3H, m).

Reference Example 146(2){2-Methyl-5-[2-(trifluoromethyl)phenyl]-3-furyl}methanol

An oily matter; ¹H-NMR (CDCl₃) δ 2.37 (3H, s), 4.52 (2H, s), 6.69 (1H,s), 7.34-7.39 (1H, m), 7.51-7.56 (1H, m), 7.70-7.73 (2H, m).

Reference Example 146(3) (2-Methyl-5-phenyl-3-furyl)methanol

an oily matter; ¹H-NMR (CDCl₃) δ 2.35 (3H, s), 4.49 (2H, s), 6.61 (1H,s), 7.18-7.24 (1H, m), 7.31-7.37 (2H, m), 7.60 (2H, d).

Reference Example 146(4) [2-Methyl-5-(4-methylphenyl)-3-furyl]methanol

Melting point 79-80° C.; ¹H-NMR (CDCl₃) δ 2.34 (6H, s), 4.49 (2H, s),6.55 (1H, s), 7.14 (2H, dd), 7.49 (2H, dd).

Reference Example 147 Ethyl 2-[(3-methoxyphenyl)thio]-2-methylpropionate

In the same manner as in Reference Example 98, an objective product wasobtained from 3-methoxybenzenethiol. An oily matter; ¹H-NMR (CDCl₃) δ1.21 (3H, t), 1.49 (6H, s) 3.78 (3H, s), 4.11 (2H, q), 6.88-6.91 (1H,m), 7.00-7.05 (2H, m), 7.18-7.25 (1H, m).

Reference Example 148 Ethyl 2-[(3-hydroxyphenyl)thio]-2-methylpropionate

In the same manner as in Reference Example 99, an objective product wasobtained from ethyl 2-[(3-methoxyphenyl)thio]-2-methylpropionateobtained in Reference Example 147.

An oily matter; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 1.49 (6H, s) 4.12 (2H,q), 5.87 (1H, s), 6.81-6.85 (1H, m), 6.95-7.02 (2H, m), 7.13-7.18 (1H,m).

Reference Example 149 Ethyl4-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]-3-oxobutanoate

To a solution of3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid (0.80g) in acetonitrile (20 ml) was added dropwise triethylamine (0.23 ml)and pivaloyl chloride (0.21 g) with ice-cooling and the mixture wasstirred for 30 minutes. Then, ethyl 4-amino-3-oxobutanoate hydrochloride(0.33 g) and triethylamine (0.23 ml) were sequentially added thereto andthe mixture was stirred at room temperature for 1.5 hours. Afterdiluting with ethyl acetate, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1 to 1:1) to obtain an objective product (0.41g) as crystals.

Melting point 131-133° C.; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.31 (3H, s),2.48 (2H, t), 2.73 (2H, t), 3.47 (2H, s), 4.18 (2H, q), 4.26 (2H, d),6.15 (1H, s), 6.58 (1H, s), 7.57 (2H, d), 7.66 (2H, d).

Reference Example 149(1) AND REFERENCE EXAMPLE 149(2)

In the same manner as in Reference Example 149, the below-describedcompounds were obtained from the ketoamino form corresponding to3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid.

Reference Example 149(1) Ethyl4-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]-3-oxopentanoate

Melting point 133-136° C.; ¹H-NMR (CDCl₃) δ 1.24 (3H, t), 1.34 (3H, d),2.30 (3H, s), 2.44 (2H, t), 2.72 (2H, t), 3.50 (2H, s), 4.15 (2H, q),4.68 (1H, quintet), 6.17 (1H, d), 6.57 (1H, s), 7.57 (2H, d), 7.66 (2H,d).

Reference Example 149(2) Ethyl5-methyl-4-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]oxohexanoate

An oily matter; ¹H-NMR (CDCl₃) δ 0.72 (3H, d), 0.92 (3H, d) 1.24 (3H,t), 2.17-2.27 (1H, m), 2.31 (3H, s), 2.49 (2H, t), 2.74 (2H, t), 3.50(2H, s), 4.16 (2H, q), 4.73 (1H, dd), 6.10 (1H, d), 6.60 (1H, s), 7.57(2H, d), 7.67 (2H, d).

Reference Example 1504-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butanoic acid

To a solution of4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butanol (1.18 g) indichloromethane (20 ml) was added triethylamine (2.21 ml) and a solutionof a sulfur trioxide pyridine complex (2.53 g) in dimethylsulfoxide (20ml) was added with ice-cooling. The mixture was stirred at roomtemperature for 30 minutes and diluted with diethyl ether. The organiclayer was washed with hydrochloric acid, water and saturated brine andthen dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain an oily matter. Theobtained oily matter was dissolved in tert-butanol (32 ml), and water (8ml), sodium dihydrogenphosphate (0.72 g) and 2-methyl-2-butene (2.1 ml)were added. Sodium chlorite (0.54 g) was finally added thereto and themixture was stirred at room temperature for 1 hour and was diluted withethyl acetate. Then, the organic layer was washed with hydrochloricacid, water and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain an oily matter. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1 to 2:1, 1:1) to obtain anobjective product (0.36 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.87-1.94 (2H, m), 2.29 (3H, s), 2.38 (2H, t), 2.43(2H, t), 6.57 (1H, s), 7.57 (2H, d), 7.66 (2H, d).

Reference Example 151 Ethyl4-[(4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butanoyl)amino]-3-oxopentanoate

In the same manner as in Reference Example 149, an objective product wasobtained from 4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butanoicacid obtained in Reference Example 150.

Amorphous; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.38 (3H, d), 1.85-1.94 (2H,m), 2.24 (2H, t), 2.29 (3H, s), 2.41 (2H, d), 3.55 (2H, s), 4.19 (2H,q), 4.70 (1H, quintet), 6.17 (1H, d), 6.58 (1H, s), 7.57 (2H, d), 7.67(2H, d).

Reference Example 152 2-(Trimethylsilyl)ethyl2-methyl-5-[(4-trifluoromethyl)phenyl]-3-furoate

To a solution of methyl 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate(4.86 g) in a mixed solvent of tetrahydrofuran-methanol (50 ml-50 ml)was added 1 N sodium hydroxide (26 ml) and the mixture was stirred at60° C. for 4 hours. After standing to cool, the mixture was acidifiedwith 1 N hydrochloric acid and diluted with ethyl acetate. The organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain an oily matter. The obtained oily matter wasdissolved in tetrahydrofuran (100 ml), and 4-dimethylaminopyridine (0.21g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride (4.92 g)and 2-(trimethylsilyl)ethanol (2.95 ml) were sequentially added. Themixture was stirred at room temperature overnight and diluted with ethylacetate. Then, the organic layer was washed with water and saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain an oily matter. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=20:1 to 10:1) to obtain an objective product (4.52 g) ascrystals. Melting point 80-81° C.; ¹H-NMR (CDCl₃) δ 0.086 (9H, s),1.07-1.16 (2H, m), 2.67 (3H, s), 4.31-4.40 (2H, m), 6.99 (1H, s), 7.62(2H, d), 7.72 (2H, d).

Reference Example 153 Ethyl 2-methyl-2-(4-methylphenoxy)propionate

In the same manner as in Reference Example 98, an objective product wasobtained from p-cresol. An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t),1.56 (6H, s) 2.27 (3H, s), 4.23 (2H, q), 6.73 (2H, d), 7.01 (2H, d).

Reference Example 154 Ethyl2-[4-(bromomethyl)phenoxy]-2-methylpropionate

To a solution of ethyl 2-methyl-2-(4-methylphenoxy)propionate (8.89 g)in ethyl acetate (100 ml) was added 2,2′-azobis(isobutyronitrile) (0.33g) in N-bromosuccinimide (7.12 g) and the mixture was heated underreflux overnight. The solvent was distilled off under reduced pressureand the residue was diluted with hexane. Insolubles were filteredthrough Celite and washed with hexane. The filtrate was distilled offunder reduced pressure to an objective product (12.13 g) as an oilymatter. An oily matter; ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 1.60 (6H, s),4.22 (2H, q), 4.46 (2H, s), 6.78 (2H, d), 7.26 (2H, d).

Reference Example 155[4-(2-Ethoxy-1,1-dimethyl-2-oxoethoxy)benzyl](triphenyl)phosphoniumbromide

To a solution of ethyl 2-[4-(bromomethyl)phenoxy]-2-methylpropionate(12.13 g) in toluene (100 ml) was added triphenylphosphine (10.5 g) andthe mixture was heated under reflux overnight. The solvent was distilledoff under reduced pressure. Diisopropyl ether was added to the residuefor crystallization, and the resultant was washed with toluene to obtainan objective product (17.37 g) as a solid matter.

Melting point 185-186° C.; ¹H-NMR (CDCl₃) δ 1.07 (3H, t), 1.48 (6H, s),4.10 (2H, q), 5.10 (2H, d), 6.62 (2H, d), 6.85 (2H, dd), 7.60-7.76 (12H,m), 7.87-7.92 (3H, m).

Reference Example 156 Ethyl3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-oxopropionate

To a solution of 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (13.0g) in tetrahydrofuran (150 ml) was added 1,1′-carbonyldiimidazole (8.2g) at room temperature and the mixture was stirred as such for 2 hours.To the mixture was added a monopotassium salt of monoethyl malonate (8.6g) and magnesium chloride (2.4 g) at room temperature and the mixturewas stirred at 60° C. overnight. The reaction solution was diluted withwater and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous sodium sulfate and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1to 6:1) to obtain an objective product (13.3 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.26-1.36 (6H, m), 3.05 (0.4H, q), 3.11 (1.6H, q), 3.79(1.6H, s), 4.23 (2H, q), 5.34 (0.2H, s), 6.81 (0.2H, s), 6.95 (0.8H, s),7.62 (0.4H, d), 7.64 (1.6H, d), 7.72 (0.4H, d), 7.74 (1.6H, d).

Reference Example 1573-{[tert-Butyl(dimethyl)silyl]oxy}-1-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-ol

To a suspension of aluminum lithium hydride (1.1 g) in tetrahydrofuran(100 ml) was added dropwise a solution of ethyl3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-oxopropionate (7.13g) in tetrahydrofuran (50 ml) with ice-cooling and the mixture wasstirred at 0° C. for 1 hour. After the reaction solution was ice-cooled,water (1 ml), a 15% aqueous sodium hydroxide solution (1 ml) and water(2.5 ml) were sequentially added dropwise thereto, and excess aluminumlithium hydride was decomposed. The mixture was stirred as such at roomtemperature for 2 hours. The produced precipitate was filtered off andwashed with ethyl acetate. The solvent of the collected filtrate wasdistilled off under reduced pressure to obtain an oily matter.

To a solution of the obtained oily matter, 4-N,N-dimethylaminopyridine(0.25 g) and triethylamine (3.4 ml) in tetrahydrofuran (100 ml) wasadded tert-butyl chlorodimethylsilane (3.0 g) at room temperature andthe mixture was stirred as such overnight. The reaction solution waspoured into water and twice extracted with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=15:1 to 9:1) to obtain an objective product (4.44 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 0.11 (6H, s), 0.93 (9H, s), 1.29 (3H, t), 1.76-1.86(1H, m), 1.98-2.12 (1H, m), 2.74 (2H, q), 3.44 (1H, d), 3.80-3.96 (2H,m), 4.89-4.96 (1H, m), 6.77 (1H, s), 7.59 (2H, d), 7.70 (2H, d).

Reference Example 158 tert-Butyl(3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methoxypropoxy)dimethylsilane

3-{[tert-Butyl(dimethyl)silyl]oxy}-1-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-ol(1.31 g) was dissolved in 1,2-dimethoxyethane (40 ml), a suspendedmatter (0.15 g) of 60% sodium hydride in liquid paraffin was added atroom temperature and the mixture was stirred as such for 0.5 hour. Tothe mixture was added methyl iodide (0.57 ml) at room temperature andthe mixture was stirred at room temperature overnight and at 60° C. for8 hours. The reaction solution was poured into water and twice extractedwith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane to hexane:ethyl acetate=15:1) to obtain anobjective product (0.87 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.04 (3H, s), 0.06 (3H, s), 0.90 (9H, s), 1.29 (3H, t),1.74-1.83 (1H, m), 2.01-2.12 (1H, m), 2.72 (2H, dq), 3.21 (3H, s),3.54-3.61 (1H, m), 3.71-3.78 (1H, m), 4.33 (1H, dd), 6.66 (1H, s), 7.59(2H, d), 7.70 (2H, d).

Reference Example 1593-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methoxy-1-propanol

To a solution of tert-butyl(3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methoxypropoxy)dimethylsilane(0.86 g) in tetrahydrofuran (5 ml) was added dropwisetetra-n-butylammonium fluoride (a 1 M tetrahydrofuran solution, 3 ml).and the mixture was stirred at room temperature for 1 hour was dilutedwith ethyl acetate. Then, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain an oilymatter. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=5:1 to 1:1) to obtain an objective product (0.54g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.29 (3H, t), 1.79-1.91 (1H, m), 2.07-2.22 (1H, m),2.46 (1H, br), 2.73 (2H, q), 3.24 (3H, s), 3.79-3.81 (2H, m), 4.39 (1H,dd), 6.70 (1H, s), 7.60 (2H, d), 7.72 (2H, d).

Reference Example 160 Di(4-hydroxyphenyl)disulfide

4-Hydroxythiophenol (5 g) was dissolved in acetone (50 ml), copper (II)nitrate trihydrate (1.9 g) was added thereto and the mixture was stirredat room temperature for 30 minutes. The solvent was distilled off, ethylacetate was added and insolubles were filtered off. The solvent of thefiltrate was distilled off and the residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane) to obtain an objectiveproduct (3.7 g) as amorphous.

¹H-NMR (CDCl₃) δ 4.98 (2H, s), 6.75 (4H, d), 7.35 (4H, d).

Reference Example 161Di(4-(1-(ethoxycarbonyl)-1-methylethoxy)phenyl)disulfide

Di(4-hydroxyphenyl)disulfide (3.7 g), ethyl 2-bromoisobutyrate (6.5 ml)and potassium carbonate (12.2 g) were heated in N,N-dimethylformamide(50 ml) at 50° C. overnight. Ethyl 2-bromoisobutyrate (3 ml) was addedthereto and the mixture was further heated overnight. The mixture waspoured into water and extracted with ethyl acetate. The organic layerwas washed with water and brine and dried over magnesium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate:hexane) toobtain an objective product (4.4 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.23 (6H, t), 1.59 (12H, s), 4.22 (4H, q), 6.75 (4H,d), 7.33 (4H, d).

Reference Example 162 N-(3-hydroxybenzyl)-N-methylglycine methyl ester

3-Hydroxybenzaldehyde (2.5 g), N-methylsarcosine methyl esterhydrochloride (2.9 g), triethylamine (3.5 ml) and sodium triacetoxyborohydride (8.7 g) were stirred in 1,2-dichloroethane (100 ml) at roomtemperature for 6 hours. The solvent was distilled off, an aqueoussodium hydrogen carbonate solution was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine and dried over magnesium sulfate, and the solvent wasdistilled off to obtain an objective product (4.3 g) as an oily matter.

¹H-NMR (CDCl₃) δ 2.39 (3H, s), 3.27 (2H, s), 3.62 (2H, s), 3.71 (3H, s),6.72-6.77 (1H, m), 6.84-6.87 (2H, m), 7.14-7.22 (1H, m).

Reference Example 163 Ethyl 3′-(benzyloxy)-1,1′-biphenyl-3-carboxylate

Ethyl 3-bromobenzoate (0.5 g), 3-benzyloxyphenyl boric acid (0.5 g), a 1M aqueous potassium carbonate solution (6 ml) and ethanol (6 ml) wasadded to toluene (50 ml) and the mixture was stirred at room temperatureunder argon atmosphere for 30 minutes. Tetrakistriphenylphosphinepalladium (80 mg) was added thereto and the mixture was refluxed for 4hours. The mixture was extracted with ethyl acetate, the organic layerwas washed with water and brine and dried over magnesium sulfate, andthe solvent was distilled off. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain an objectiveproduct (0.65 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.41 (3H, t), 4.40 (2H, q), 5.13 (2H, s), 6.97-7.01(1H, m), 7.20-7.25 (1H, m), 7.33-7.51 (1H, m), 7.73-7.77 (1H, m),8.00-8.03 (1H, m), 8.25-8.26 (1H, m).

Reference Example 164 Ethyl 3′-hydroxy-1,1′-biphenyl-3-carboxylate

Ethyl 3′-(benzyloxy)-1,1′-biphenyl-3-carboxylate (0.65 g) was dissolvedin ethanol (50 ml) and the solution was catalytically reduced using 10%palladium-carbon (50% water content, 0.1 g) overnight. A catalyst wasfiltered off and the solvent of the filtrate was distilled off to obtainan objective product (0.4 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.42 (3H, t), 4.41 (2H, q), 5.00 (1H, br), 6.85 (1H,dd), 7.09-7.11 (1H, m), 7.17-7.22 (1H, m), 7.30-7.38 (1H,m), 7.46-7.54(1H, m), 7.73-7.79 (1H, m), 8.00-8.06 (1H, m), 8.25-8.26 (1H, m).

Reference Example 165 Methyl [3′-(benzyloxy)-1,1′-biphenyl-3-yl]acetate

Methyl m-hydroxyphenyl acetate (1.7 g) and triethylamine (2.9 ml) wasdissolved in dichloromethane (50 ml), and trifluoromethanesulfonicanhydride (1.8 ml) was added dropwise thereto with ice-cooling. Themixture was stirred for 15 minutes, the reaction solution was washedwith water and dried and the solvent was distilled off. A half amount ofthe residue was dissolved in toluene (50 ml,) and 3-benzyloxyphenylboric acid (0.5 g), a 1 M aqueous potassium carbonate solution (6 ml)and ethanol (6 ml) was added thereto. The mixture was stirred at roomtemperature under argon atmosphere for 30 minutes.

Tetrakistriphenylphosphine palladium (100 mg) was added thereto and themixture was refluxed overnight. The mixture was extracted with ethylacetate, the organic layer was washed with water and brine and driedover magnesium sulfate, and the solvent was distilled off. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain an objective product (0.69 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.67-3.71 (5H, m), 5.12 (2H, s), 6.94-6.98 (1H, m),7.16-7.49 (12H, m).

Reference Example 166 Methyl (3′-hydroxy-1,1′-biphenyl-3-yl)acetate

Methyl 3′-(benzyloxy)-1,1′-biphenyl-3-yl]acetate (0.69 g) was dissolvedin ethanol (50 ml) and ethyl acetate (10 ml), and the mixture wascatalytically reduced using 10% palladium-carbon (50% water content, 0.8g) for 6 hours. A catalyst was filtered off and the solvent of thefiltrate was distilled off. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain an objectiveproduct (0.27 g) as an oily matter.

¹H-NMR (CDCl₃) δ 3.69-3.71 (5H, m), 4.81 (1H, s), 6.81 (1H, d), 7.04(1H, s), 7.15 (1H, d), 7.25-7.32 (2H, m), 7.35-7.41 (1H, m), 7.45-7.48(2H, m).

Reference Example 167 Methyl 2-methyl-2-[(4-nitrobenzyl)thio]propionate

4-Nitrobenzyl bromide (1.8 g), methyl 2-mercaptoisobutyrate (1.16 g) andpotassium carbonate (2.4 g) were stirred in DMF (10 ml) at roomtemperature for 1 hour. The mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with water and brineand dried over magnesium sulfate, and the solvent was distilled off toobtain an objective product (2.2 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.54 (6H, s), 3.63 (3H, s), 3.90 (2H, s), 7.48 (2H, d),8.15 (2H, d).

Reference Example 168 Methyl 2-[(4-aminobenzyl)thio]-2-methylpropionate

Methyl 2-methyl-2-[(4-nitrobenzyl)thio]propionate (2.2 g) and reducediron (2.3 g) were stirred at room temperature in acetic acid (50 ml)overnight. The solvent was distilled off and ethyl acetate was added.Insolubles were filtered through Celite, the filtrate was washed with anaqueous sodium hydrogen carbonate solution, water and brine and thendried over magnesium sulfate, and the solvent was distilled off. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain an objective product (1.4 g) as an oilymatter.

¹H-NMR (CDCl₃) δ 1.53 (6H, s), 3.63 (2H, br), 3.67 (3H, s), 3.73 (2H,s), 6.60 (2H, d), 7.07 (2H, d).

Example 1[(3{[5-(4-Fluorophenyl)-2-methyl-3-furoyl]amino}benzyl)thio]acetic acid

To a solution of5-(4-fluorophenyl)-N-[3-(hydroxymethyl)phenyl]-2-methyl-3-furancarboxamide(0.26 g) and triethylamine (0.33 ml) in tetrahydrofuran (10 ml) wasadded dropwise methanesulfonyl chloride (68 μl) at room temperature andthe mixture was stirred as such for 0.5 hour. To the obtained mixturewas added ethyl thioglycollate (0.10 ml) was added at room temperatureand the mixture was stirred as such overnight. The solvent of thereaction solution was distilled off under reduced pressure and theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=9:1 to 3:1) to obtain a solid matter. The obtainedsolid matter was dissolved in methanol (3 ml) and tetrahydrofuran (5ml). A 1 N aqueous sodium hydroxide solution (1.6 ml) was added and thenthe mixture was stirred at room temperature overnight. The reactionsolution was concentrated and diluted with water. The reaction solutionwas acidified with hydrochloric acid and twice extracted with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure. Theobtained crude product was crystallized from hexane to obtain anobjective product (0.11 g) as powders. Melting point 198-199° C.; ¹H-NMR(CDCl₃-CD₃OD) δ 2.70 (3H, s), 3.11 (2H, s), 3.85 (2H, s), 7.06-7.14 (4H,m), 7.29 (1H, t), 7.61-7.70 (4H, m), 8.88 (1H, s).

Example 1(1) to Example 1(5)

In the same manner as in Example 1, the below-described compounds wereobtained from the compounds obtained in Reference Example 17(1) toReference Example 17(5).

Example 1(1)[(3{[5-(4-Fluorophenyl)-2-methyl-3-furoyl](methyl)amino}benzyl)thio]aceticacid

Melting point 155-156° C.; ¹H-NMR (CDCl₃) δ 2.49 (3H, s) 2.81 (2H, s),3.45 (3H, s), 3.78 (2H, s), 5.68 (1H, s), 6.97 (2H, t), 7.12-7.15 (2H,m), 7.22-7.39 (4H, m).

Example 1(2)[(3{[5-(4-Fluorophenyl)-2-methyl-3-furoyl](propyl)amino}benzyl)thio]aceticacid

Melting point 140-141° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t) 1.55-1.74 (2H,m), 2.49 (3H, s), 2.78 (2H, s), 3.78 (2H, s), 3.83 (2H, t), 5.63 (1H,s), 6.96 (2H, t), 7.10-7.25 (2H, m), 7.23-7.39 (4H, m).

Example 1(3)[(3{[5-(4-Fluorophenyl)-2-methyl-3-furoyl](heptyl)amino}benzyl)thio]aceticacid

Melting point 94-96° C.; ¹H-NMR (CDCl₃) δ 0.86 (3H, t), 1.25-1.34 (10H,m), 1.56-1.65 (2H, m), 2.48 (3H, s), 2.78 (2H, s), 3.77 (2H, s), 3.84(2H, t), 5.62 (1H, s), 6.96 (2H, t), 7.08-7.13 (2H, m), 7.23-7.36 (4H,m).

Example 1(4)[(3{Benzyl[5-(4-fluorophenyl)-2-methyl-3-furoyl]amino}benzyl)thio]aceticacid

An oily matter; ¹H-NMR (CD₃OD) δ 2.53 (3H, s), 2.69 (2H, s), 3.69 (2H,s), 5.08 (2H,'s), 5.63 (1H, s), 6.91-7.03 (4H, m), 7.17-7.31 (9H, m).

Example 1(5){[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzyl]thio}aceticacid

Melting point 188-189° C.; ¹H-NMR (CDCl₃) δ 2.72 (3H, s) 3.10 (2H, s),3.85 (2H, s), 7.08-7.18 (2H, m), 7.26-7.34 (1H, m), 7.59-7,70 (3H, m),7.77 (2H, d), 8.42 (1H, s).

Example 2{[3-({2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzyl]thio}aceticacid

Ethyl [(3-aminobenzyl)thio]acetate.hydrochloride (0.41 g) was dissolvedin water and the solution was alkalified with potassium carbonate andtwice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure to obtain ethyl [(3-aminobenzyl)thio]acetateas an oily matter.

To a solution of2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furancarboxylate (0.45 g) andN,N-dimethylformamide (1 drop) in tetrahydrofuran (10 ml) was addeddropwise oxalyl chloride (0.28 ml) at room temperature and the mixturewas stirred for 0.5 hour. The solvent of the reaction solution wasdistilled off under reduced pressure to obtain a crude product of acidchloride as a solid matter. The above obtained ethyl[(3-aminobenzyl)thio]acetate and sodium hydrogen carbonate (0.27 g) werestirred in tetrahydrofuran (20 ml) and the obtained acid chloride wasdissolved in tetrahydrofuran (10 ml). The mixture was added dropwise atroom temperature and stirred as such overnight. The reaction solutionwas diluted with ethyl acetate, washed with water and dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure to obtain an oily matter. The obtained oilymatter was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml) and a1 N aqueous sodium hydroxide solution (3 ml) was added thereto. Themixture was stirred at room temperature overnight. The reaction solutionwas concentrated and diluted with water. The reaction solution wasacidified with hydrochloric acid and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous sodium sulfate andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was crystallized from diisopropyl ether-hexane to obtain anobjective product (0.62 g) as crystals.

Melting point 199-200° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 1.36 (3H, t), 3.10(2H, s), 3.16 (2H, q), 3.85 (2H, s), 7.10 (1H, d), 7.15 (1H, s), 7.29(1H, t), 7.58 (1H, s), 7.64 (2H, d), 7.67 (1H, d), 7.77 (2H, d), 8.33(1H, s).

Example 2(1) to Example 2(5)

In the same manner as in Example 2, ethyl[(3-aminobenzyl)thio]acetate.hydrochloride was condensed with thecorresponding carboxylic acid (as synthesized in Reference Example, oras commercially available) and hydrolyzed to obtain the below-describedcompounds.

Example 2(1){[3-({2-Isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzyl]thio}aceticacid

Melting point 173-174° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 1.38 (6H, d), 3.10(2H, s), 3.85 (2H, s), 3.89-3.98 (1H, m), 7.10 (1H, d), 7.11 (1H, s),7.29 (1H, t), 7.58 (1H, s), 7.64 (2H, d), 7.67 (1H, d), 7.76 (2H, d),8.26 (1H, s).

Example 2(2){[3-({2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzyl]thio}aceticacid

Melting point 195-196° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 0.96 (3H, t),1.38-1.50 (2H, m), 1.72-1.82 (2H, m), 3.10 (2H, s), 3.14 (2H, t), 3.85(2H, s), 7.09-7.17 (2H, m), 7.29 (1H, t), 7.56 (1H, s), 7.64 (2H, d),7.67 (1H, d), 7.76 (2H, d), 8.31 (1H, s).

Example 2(3) [(3-{[5-(4-Chlorophenyl)-2-furoyl]amino}benzyl]thio]aceticacid

Melting point 173-174° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 3.11 (2H, s), 3.86(2H, s), 6.79 (1H, d), 7.12 (1H, d), 7.29-7.34 (2H, m), 7.42 (2H, d),7.61 (1H, t), 7.73-7.78 (3H, m), 8.65 (1H, s).

Example 2(4)({3-[(3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionyl)amino)benzyl}thio) acetic acid

¹H-NMR (CDCl₃) δ 2.33 (3H, s), 2.59 (2H, t), 2.80 (2H, t), 3.07 (2H, s),3.80 (2H, s), 6.65 (1H, s), 7.04 (1H, d), 7.24 (1H, t), 7.46 (1H, s),7.56 (3H, m), 7.67 (2H, d), 8.57 (1H, br s).

Example 2(5)({3-[(3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionyl) amino)benzyl}thio) acetic acid

Melting point 137-138° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 0.93 (3H, t),1.32-1.42 (2H, m), 1.59-1.69 (2H, m), 2.59 (2H, t), 2.66 (2H, t), 2.81(2H, t), 3.07 (2H, s), 3.80 (2H, s), 6.65 (1H, s), 7.04 (2H, d), 7.24(1H, t), 7.44 (1H, s), 7.56 (3H, d), 7.66 (2H, d), 8.39 (1H, s).

Example 3[(3-{[5-Phenyl-2-(trifluoromethyl)-3-furoyl]amino}benzyl)thio]aceticacid

While ethyl [(3-aminobenzyl)thio]acetate hydrochloride (0.21 g),5-phenyl-2-(trifluoromethyl)-3-furancarboxylic acid (0.21 g) andtriethylamine (0.28 ml) were stirred in tetrahydrofuran (10 ml) andN,N-dimethylformamide (2 ml), diethyl phosphorocyanidate (0.14 ml) wasadded dropwise thereto at room temperature and the mixture was stirredas such overnight. The reaction solution was poured into an aqueoussodium hydrogen carbonate solution and twice extracted with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was distilled off under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane:ethyl acetate=3:1 to 1:1) to obtain an oily matter. The obtainedoily matter was dissolved in methanol (3 ml) and tetrahydrofuran (3 ml),a 1 N aqueous sodium hydroxide solution (1 ml) was added thereto and themixture was stirred at room temperature overnight. The reaction solutionwas concentrated and diluted with water. The reaction solution wasacidified with hydrochloric acid and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous sodium sulfate andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was crystallized from diisopropyl ether-hexane to obtain anobjective product (60 mg) as powders.

Melting point 178-182° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 3.10 (2H, s), 3.85(2H, s), 7.12 (1H, d), 7.21 (1H, s), 7.30 (1H, t), 7.39-7.51 (3H, m),7.67-7.77 (4H, m), 9.50 (1H, s).

Example 4({3-[(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]benzyl}thio)aceticacid

While ethyl [(3-aminobenzyl)thio]acetate. hydrochloride (0.20 g),3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propionic acid (0.24g), 1-hydroxybenzotriazole hydrate (0.14 g) and triethylamine (0.16 ml)was stirred in N,N-dimethylformamide (5 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride (0.18 g) wasadded thereto at room temperature, and then the mixture was stirred assuch overnight. The reaction solution was poured into an aqueous sodiumhydrogen carbonate solution and twice extracted with ethyl acetate. Thecollected organic layer was dried over anhydrous sodium sulfate and thesolvent was distilled off under reduced pressure. The obtained residuewas dissolved in methanol (3 ml) and tetrahydrofuran (3 ml), a 1 Naqueous sodium hydroxide solution (2 ml) was added and then the mixturewas stirred at room temperature overnight. The reaction solution wasconcentrated and diluted with water. The reaction solution was acidifiedwith dilute hydrochloric acid and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous sodium sulfate andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was crystallized from diisopropyl ether to obtain an objectiveproduct (0.12 g) as powders. Melting point 139-141° C.; ¹H-NMR(CDCl₃-DMSO-d₆) δ 1.26 (3H, t), 2.58 (2H, t), 2.70 (2H, q), 2.82 (2H,t), 3.07 (2H, s), 3.80 (2H, s), 6.64 (1H, s), 7.07 (1H, d), 7.26 (1H,t), 7.41 (1H, s), 7.53 (1H, d), 7.57 (2H, d), 7.68 (2H, d), 7.90 (1H,s).

Example 4(1) and Example 4(2)

In the same manner as in Example 4, ethyl[(3-aminobenzyl)thio]acetate.hydrochloride was condensed with thecorresponding carboxylic acid (as synthesized in Reference Example) andhydrolyzed to obtain the below-described compounds.

Example 4(1)({3-[({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}acetyl)amino]benzyl}thio)aceticacid

Melting point 173-174° C.; ¹H-NMR (CDCl₃) δ 2.40 (3H, s), 3.07 (2H, s),3.49 (2H, s), 3.80 (2H, s), 6.78 (1H, s), 7.06 (1H, d), 7.24 (1H, t),7.45 (1H, s), 7.54-7.61 (3H, m), 7.71 (2H, d), 8.50 (1H, s).

Example 4(2)({3-[({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)benzyl]thio}aceticacid

Melting point 200-202° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.71 (3H, s), 3.10(2H, s), 3.85 (2H, s), 7.97-7.10 (1H, m), 7.19-7.31 (4H, m), 7.64-7.72(4H, m), 8.94 (1H, s).

Example 5[(3-{[4-(4-Fluorophenyl)-2,5-dimethyl-3-furyl]methoxy}benzyl)thio]aceticacid

To a solution of [4-(4-fluorophenyl)-2,5-dimethyl-3-furyl]methanol (0.29g), ethyl [(3-hydroxybenzyl)thio]acetate (0.32 g) and tributylphosphine(0.39 ml) in tetrahydrofuran (20 ml) was added a solution of diethylazodicarboxylate in 40% toluene (0.68 g) at room temperature and themixture was stirred overnight. The solvent of the reaction solution wasdistilled off under reduced pressure and the obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 6:1) to obtain an oily matter. The obtained oily matter was dissolvedin methanol (3 ml) and tetrahydrofuran (3 ml), a 1 N aqueous sodiumhydroxide solution (1.3 ml) was added thereto, and then the mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated and diluted with water. The reaction solution was acidifiedwith dilute hydrochloric acid and twice extracted with ethyl acetate.The collected organic layer was dried over anhydrous sodium sulfate andthe solvent was distilled off under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane:ethylacetate=1:1 to ethyl acetate) to obtain an objective product (66 mg) asan oily matter.

¹H-NMR (CDCl₃) δ 2.28 (3H, s), 2.33 (3H, s), 3.12 (2H, s), 3.81 (2H, s),4.69 (2H, s), 6.79-6.95 (3H, m), 7.03 (2H, t), 7.23 (1H, t), 7.30 (2H,dd).

Example 5(1) to Example 5(12)

In the same manner as in Example 5, the corresponding furanalkanol (assynthesized in Reference Example) was condensed with the correspondingphenol (the compound synthesized in Reference Example or the alreadyknown compound) and hydrolyzed to obtain the below-described compounds.

Example 5(1)[(3-{[4-(4-Fluorophenyl)-2-isopropyl-5-methyl-3-furyl]methoxy}benzyl)thio]aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.29 (6H, d), 2.29 (3H, s) 3.04-3.18(1H, m), 3.12 (2H, s), 3.81 (2H, s), 4.70 (2H, s), 6.79-6.94 (3H, m),7.03 (2H, t), 7.22 (1H, t), 7.31 (2H, dd).

Example 5(2)[(3-{[2-Dichlorohexyl-4-(4-fluorophenyl)-5-methyl-3-furyl]methoxy}benzyl)thio]aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.20-1.45 (2H, m), 1.55-1.85 (8H, m),2.28 (3H, s), 2.65-2.80 (1H, m), 3.13 (2H, s), 3.81 (2H, s), 4.70 (2H,s), 6.80-6.95 (3H, m), 7.02 (2H, t), 7.23 (1H, t), 7.31 (2H, dd).

Example 5(3)[(3-{[4-(4-Fluorophenyl)-5-methyl-2-phenyl-3-furyl]methoxy}benzyl)thio]aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 2.41 (3H, s), 3.14 (2H, s), 3.82 (2H,s), 4.80 (2H, s), 6.86-6.98 (3H, m), 7.06 (2H, t), 7.22-7.44 (6H, m),7.66-7.70 (2H, m).

Example 5(4)[(3-{[5-Phenyl-2-(trifluoromethyl)-3-furyl]methoxy}benzyl)thio]aceticacid

Melting point 84-85° C.; ¹H-NMR (CDCl₃) δ 3.11 (2H, s), 3.84 (2H, s),5.09 (2H, s), 6.85 (1H, s), 6.87-6.99 (3H, m), 7.27 (1H, t), 7.34-7.46(3H, m), 7.67-7.73 (2H, m).

Example 5(5){[3-(2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl)methoxy)benzyl]thio}aceticacid

Melting point 93-94° C.; ¹H-NMR (CDCl₃) δ 1.31 (3H, t), 2.77 (2H, q),3.12 (2H, s), 3.83 (2H, s), 4.88 (2H, s), 6.78 (1H, s), 6.86-6.97 (3H,m), 7.25 (1H, t), 7.59 (2H, d), 7.70 (2H, d).

Example 5(6){[3-(2-Isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl)methoxy)benzyl]thio}aceticacid

Melting point 84-85° C.; ¹H-NMR (CDCl₃) δ 1.34 (6H, d), 3.12 (2H, s),3.12-3.21 (1H, m), 3.83 (2H, s), 4.89 (2H, s), 6.77 (1H, s), 6.88 (1H,dd), 6.93-6.97 (2H, m), 7.25 (1H, t), 7.59 (2H, d), 7.70 (2H, d)

Example 5(7){[3-(2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl)methoxy)benzyl]thio}aceticacid

Melting point 77-78° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t), 1.34-1.46 (2H,m), 1.64-1.74 (2H, m), 2.73 (2H, t), 3.12 (2H, s), 3.83 (2H, s), 4.87(2H, s), 6.79 (1H, s), 6.87-6.97 (3H, m), 7.26 (1H, t), 7.59 (2H, d),7.70 (2H, d).

Example 5(8)3-(4-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenyl)propionicacid

Melting point 123-125° C.; ¹H-NMR (CDCl₃) δ 2.31 (3H, s) 2.37 (3H, s),2.62 (2H, t), 2.91 (2H, t), 4.82 (2H, s), 6.58 (1H, s), 6.74-6.80 (2H,m), 7.04 (2H, t), 7.07 (1H, d), 7.57 (2H, dd).

Example 5(9)3-[4-({2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-2-methylphenyl]propionicacid

Melting point 95-97° C.; ¹H-NMR (CDCl₃) δ 1.30 (3H, t), 2.31 (3H, s),2.62 (2H, t), 2.76 (2H, q), 2.91 (2H, t), 4.84 (2H, s), 6.74-6.79 (3H,m), 7.08 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 5(10)3-[4-({2-Isopropyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-2-methylphenyl]propionicacid

Melting point 108-109° C.; ¹H-NMR (CDCl₃) δ 1.33 (6H, d), 2.31 (3H, s),2.62 (2H, t), 2.91 (2H, t), 3.10-3.20 (1H, m), 4.85 (2H, s), 6.74-6.79(3H, m), 7.08 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 5(11)3-[4-({2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-2-methylphenyl]propionicacid

Melting point 118-119° C.; ¹H-NMR (CDCl₃) δ 0.94 (3H, t), 1.36-1.45 (2H,m), 1.63-1.73 (2H, m), 2.31 (3H, s), 2.62 (2H, t), 2.72 (2H, t), 2.91(2H, t), 4.83 (2H, s), 6.74-6.79 (3H, m), 7.08 (1H, d), 7.59 (2H, d),7.70 (2H, d).

Example 5(12)3-(2-Methyl-4-{[5-phenyl-2-(trifluoromethyl)-3-furyl]methoxy}phenyl)propionicacid

Melting point 151-152° C.; ¹H-NMR (CDCl₃) δ 2.31 (3H, s), 2.61 (2H, t),2.90 (2H, t), 5.05 (2H, s), 6.73-6.82 (3H, m), 7.08 (1H, d), 7.31-7.44(3H, m), 7.68-7.71 (2H, m).

Example 62-[(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]-2-methylpropionicacid

To a solution of [5-(4-fluorophenyl)-2-methyl-3-furyl]methanol (1.05 g),ethyl 2-[(3-hydroxybenzyl)thio]-2-methylpropionate (1.29 g) andtributylphosphine (2.05 g) in tetrahydrofuran (100 ml) was added1,1′-(azodicarbonyl)dipiperidine (2.56 g) at room temperature and themixture was stirred overnight. The solvent of the reaction solution wasdistilled off under reduced pressure and diisopropyl ether was addedthereto. The precipitate was filtered off and washed with diisopropylether. The solvent of the filtrate was distilled off under reducedpressure and the obtained crude product was purified by silica gelcolumn chromatography (hexane:ethyl acetate=30:1 to 9:1) to obtain anoily matter. The obtained oily matter was dissolved in methanol (30 ml)and tetrahydrofuran (30 ml), a 1 N aqueous sodium hydroxide solution (10ml) was added thereto and the mixture was stirred at room temperatureovernight. The reaction solution was concentrate and diluted with water.The reaction solution was acidified with dilute hydrochloric acid andtwice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous sodium sulfate and the solvent was distilled offunder reduced pressure. The obtained crude product was crystallized fromdiisopropyl ether-hexane to obtain an objective product (1.49 g) ascrystals.

Melting point 134-135° C.; ¹H-NMR (CDCl₃) δ 1.56 (6H, s), 2.37 (3H, s),3.88 (2H, s), 4.84 (2H, s), 6.58 (1H, s), 6.84 (1H, dd), 6.91-6.96 (2H,m), 7.04 (2H, t), 7.21 (1H, t), 7.58 (2H, dd).

Example 6(1) to Example 6(126)

In the same manner as in Example 6, the corresponding furanalkanol (assynthesized in Reference Example) was condensed with the correspondingphenol (the compound synthesized in Reference Example or the alreadyknown compound) and hydrolyzed to obtain the below-described compounds.

Example 6(1)[(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]aceticacid

Melting point 120-122° C.; ¹H-NMR (CDCl₃) δ 2.39 (3H, s) 3.12 (2H, s),3.84 (2H, s), 4.87 (2H, s), 6.60 (1H, s), 6.86-6.97 (3H, m), 7.05 (2H,t), 7.26 (1H, t), 7.59 (2H, dd).

Example 6(2){[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Amorphous; ¹H-NMR (CDCl₃) δ 2.41 (3H, s), 3.11 (2H, s), 3.83 (2H, s),4.97 (2H, s), 6.78 (1H, s), 6.86-6.89 (1H, m), 6.93-6.97 (2H, m),7.22-7.27 (1H, m), 7.58 (2H, d), 7.69 (2H, d).

Example 6(3)[2-Methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]aceticacid

Melting point 147-149° C.; ¹H-NMR (CDCl₃) δ 2.30 (3H, s) 2.39 (3H, s),3.61 (2H, s), 4.83 (2H, s), 6.76-6.82 (3H, m), 7.12 (1H, d), 7.59 (2H,d), 7.70 (2H, d).

Example 6(4)3-[2-Methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 140-141° C.; ¹H-NMR (CDCl₃) δ 2.31 (3H, s) 2.40 (3H, s),2.61 (2H, t), 2.90 (2H, t), 4.83 (2H, s), 6.73-6.79 (3H, m), 7.08 (1H,d), 7.58 (2H, d), 7.69 (2H, d).

Example 6(5)2-Methyl-2-[4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propionicacid

Melting point 134-135° C.; ¹H-NMR (CDCl₃) δ 1.54 (6H, s), 2.39 (3H, s),4.83 (2H, s), 6.76 (1H, s), 6.86-6.95 (4H, m), 7.59 (2H, d) 7.70 (2H,d).

Example 6(6)3-[2-Methoxy-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 159-160° C.; ¹H-NMR (CDCl₃) δ 2.40 (3H, s), 2.63 (2H, t),2.88 (2H, t), 3.78 (3H, s), 4.83 (2H, s), 6.46-6.49 (2H, m), 6.77 (1H,s), 7.07 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 6(7)[4-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

Melting point 168-169° C.; ¹H-NMR (CDCl₃) δ 2.38 (3H, s) 4.55 (2H, s),4.81 (2H, s), 6.77 (1H, s) 6.88 (4H, s), 7.59 (2H, d), 7.70 (2H, d).

Example 6(8)[4-(3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 113-114° C.; ¹H-NMR (CDCl₃) δ 1.98-2.05 (2H, m), 2.27 (3H,s), 2.57 (2H, t), 3.59 (2H, s), 3.94 (2H, t), 6.59 (1H, s), 6.86 (2H,d), 7.19 (2H, d), 7.57 (2H, t), 7.67 (2H, d).

Example 6(9)[4-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]aceticacid

Melting point 147-149° C.; ¹H-NMR (CDCl₃) δ 2.39 (3H, s) 3.60 (2H, s),4.85 (2H, s), 6.77 (1H, s), 6.92 (2H, d), 7.20 (2H, d), 7.59 (2H, d),7.70 (2H, d).

Example 6(10)[2-Methoxy-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]aceticacid

Melting point 168-169° C.; ¹H-NMR (CDCl₃) δ 2.41 (3H, s) 3.61 (2H, s),3.80 (3H, s), 4.85 (2H, s), 6.53-6.55 (2H, m), 6.79 (1H, s), 7.11 (1H,d), 7.60 (2H, d), 7.71 (2H, d).

Example 6(11)[(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}benzyl)oxy]acetic acid

Melting point 109-110° C.; ¹H-NMR (CDCl₃) δ 2.38 (3H, s), 4.14 (2H, s),4.64 (2H, s), 4.86 (2H, s), 6.59 (1H, s), 6.92-6.98 (3H, m), 7.04 (2H,t), 7.30 (1H, t), 7.58 (2H, dd).

Example 6(12){[3-(3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)benzyl]thio}aceticacid

Melting point 106-107° C.; ¹H-NMR (CDCl₃) δ 0.89 (3H, t), 1.27-1.39 (2H,m), 1.56-1.66 (2H, m), 1.98-2.07 (2H, m), 2.58 (2H, t), 2.61 (2H, t),3.11 (2H, s), 3.81 (2H, s), 3.96 (2H, t), 6.60 (1H, s), 6.79-6.82 (1H,m), 6.89-6.91 (2H, m), 7.22 (1H, t), 7.57 (2H, d), 7.66 (2H, d).

Example 6(13)[4-(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)phenyl]aceticacid

Melting point 115-116° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s) 2.84 (2H, t),3.58 (2H, s), 4.08 (2H, t), 6.66 (1H, s), 6.86 (2H, d), 7.18 (2H, d),7.57 (2H, d), 7.68 (2H, d).

Example 6(14){4-Methyl-2-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-1,3-thiazol-5-yl}aceticacid

Melting point 175-176° C.; ¹H-NMR (CDCl₃) δ 2.32 (3H, s) 2.34 (3H, s),3.67 (2H, s), 4.15 (2H, s), 6.70 (1H, s), 7.57 (2H, d), 7.67 (2H, d).

Example 6(15)[3-(3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 80-82° C.; ¹H-NMR (CDCl₃) δ 0.89 (3H, t), 1.26-1.39 (2H,m), 1.56-1.66 (2H, m), 1.97-2.06 (2H, m), 2.57 (2H, t), 2.60 (2H, t),3.61 (2H, s), 3.95 (2H, t), 6.59 (1H, s), 6.79-6.87 (3H, m), 7.23 (1H,t), 7.56 (2H, d), 7.66 (2H, d).

Example 6(16)[4-(3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 96-97° C.; ¹H-NMR (CDCl₃) δ 0.89 (3H, t), 1.27-1.39 (2H,m), 1.56-1.66 (2H, m), 1.97-2.06 (2H, m), 2.57 (2H, t), 2.60 (2H, t),3.59 (2H, s), 3.94 (2H, t), 6.59 (1H, s), 6.85 (2H, d), 7.18 (2H, d),7.57 (2H, d), 7.66 (2H, d)

Example 6(17){2-[(3-{2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)thio]-4-methyl-1,3-thiazol-5-yl}aceticacid

Melting point 93-94° C.; ¹H-NMR (CDCl₃) δ 0.93 (3H, t), 1.31-1.43 (2H,m), 1.59-1.69 (2H, m), 1.95-2.04 (2H, m), 2.32 (3H, s), 2.53 (2H, t),2.62 (2H, t), 3.14 (2H, t), 3.73 (2H, s), 6.57 (1H, s), 7.57 (2H, d),7.66 (2H, d).

Example 6(18)[2-({[5-(4-Fluorophenyl)-2-methyl-3-furyl]methyl}thio)-4-methyl-1,3-thiazol-5-yl]aceticacid

Melting point 202-205° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.30 (3H, s), 2.34(3H, s), 3.67 (2H, s), 4.15 (2H, s), 6.52 (1H, s), 7.03 (2H, t), 7.55(2H, dd).

Example 6(19)4-(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}phenyl)butanoic acid

Melting point 98-99° C.; ¹H-NMR (CDCl₃) δ 1.89-2.04 (2H, m), 2.38 (2H,t), 2.66 (2H, t), 4.84 (2H, s), 6.60 (1H, s), 6.79-6.84 (3H, m), 7.05(2H, t), 7.22 (1H, t), 7.59 (2H, dd).

Example 6(20){[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)benzyl]thio}aceticacid

Melting point 106-107° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 1.98-2.07 (2H,m), 2.58 (2H, t), 2.64 (2H, q), 3.11 (2H, s), 3.81 (2H, s), 3.96 (2H,t), 6.59 (1H, s), 6.78-6.81 (1H, m), 6.89 (1H, s), 6.90 (1H, d), 7.22(1H, t), 7.57 (2H, d), 7.67 (2H, d).

Example 6(21){[3-({2-Methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 84-85° C.; ¹H-NMR (CDCl₃) δ 2.39 (3H, s), 3.11 (2H, s),3.83 (2H, s), 4.86 (2H, s), 6.66 (1H, s), 6.86-6.97 (3H, m), 7.19 (2H,d), 7.25 (1H, t), 7.62 (2H, d).

Example 6(22)3-[2-Methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)phenyl]propionicacid

Melting point 118-120° C.; ¹H-NMR (CDCl₃) δ 2.28 (3H, s), 2.34 (3H, s),2.59 (2H, t), 2.81-2.90 (4H, m), 4.06 (2H, t), 6.61-6.71 (3H, m), 7.04(1H, d), 7.57 (2H, d), 7.67 (2H, d).

Example 6(23)[4-(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)phenoxy]aceticacid

Melting point 132-133° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 2.83 (2H, d),4.05 (2H, d), 4.62 (2H, s), 6.65 (1H, s), 6.81-6.85 (4H, m), 7.57 (2H,d), 7.67 (2H, d).

Example 6(24)3-[2-Methyl-4-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]propionicacid

Melting point 125-126° C.; ¹H-NMR (CDCl₃) δ 1.95-2.04 (2H, m), 2.27 (3H,s), 2.28 (3H, m), 2.53-2.63 (4H, m), 2.88 (2H, t), 3.92 (2H, d), 6.59(1H, s), 6.48-6.71 (2H, m), 7.02 (1H, d), 7.56 (2H, d), 7.66 (2H, d).

Example 6(25)[4-(3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenoxy]aceticacid

Melting point 134-135° C.; ¹H-NMR (CDCl₃) δ 1.98-2.04 (2H, m), 2.26 (3H,s), 2.56 (2H, t), 3.90 (2H, t), 4.62 (2H, s), 6.58 (1H, s), 6.81-6.88(4H, m), 7.56 (2H, d), 7.66 (2H, d).

Example 6(26)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 113-114° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 1.97-2.06 (2H,m), 2.58 (2H, t), 2.64 (2H, q), 3.61 (2H, s), 3.96 (2H, t), 6.59 (1H,s), 6.79-6.86 (3H, m), 7.23 (1H, t), 7.57 (2H, d), 7.66 (2H, d).

Example 6(27)[4-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 121-122° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.97-2.06 (2H,m), 2.57 (2H, t), 2.64 (2H, q), 3.59 (2H, s), 3.95 (2H, t), 6.59 (1H,s), 6.85 (2H, d), 7.18 (2H, d), 7.57 (2H, d), 7.66 (2H, d).

Example 6(28){2-[(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)thio]-4-methyl-1,3-thiazol-5-yl}aceticacid

Melting point 99-100° C.; ¹H-NMR (CDCl₃) δ 1.25 (3H, t) 1.94-2.05 (2H,m), 2.31 (3H, s), 2.53 (2H, t), 2.66 (2H, q), 3.14 (2H, t), 3.73 (2H,s), 6.57 (1H, s), 7.57 (2H, d), 7.67 (2H, d)

Example 6(29)[(3-{1-[5-(4-Fluorophenyl)-2-methyl-3-furyl]ethoxy}benzyl)thio]aceticacid

Amorphous powders; ¹H-NMR (CDCl₃) δ 1.62 (3H, d), 2.34 (3H, s), 3.02(2H, s), 3.78 (2H, s), 5.26 (1H, q), 6.55 (1H, s), 6.77-6.90 (3H, m),7.02 (2H, t), 7.19 (1H, t), 7.55 (2H, dd).

Example 6(30)[(3-{1-[5-(4-Fluorophenyl)-2-methyl-3-furyl]butoxy}benzyl)thio]aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 0.96 (3H, t), 1.33-1.58 (2H, m),1.70-1.87 (1H, m), 1.94-2.09 (1H, m), 2.34 (3H, s), 3.00 (2H, s), 3.77(2H, s), 5.04 (1H, t), 6.51 (1H, s), 6.75-6.88 (3H, m), 7.02 (2H, t),7.17 (1H, t), 7.54 (2H, dd).

Example 6(31)2-Methyl-2-[4-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenoxy]propionicacid

Melting point 123-124° C.; ¹H-NMR (CDCl₃) δ 1.54 (6H, s) 1.97-2.04 (2H,m), 2.26 (3H, s), 2.57 (2H, t), 3.92 (2H, t), 6.59 (1H, s), 6.76-6.94(4H, m), 7.57 (2H, d), 7.66 (2H, d).

Example 6(32){4-Methyl-2-[(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)thio]-1,3-thiazol-5-yl}aceticacid

Melting point 130-132° C.; ¹H-NMR (CDCl₃) δ 2.31, 2.32 (6H, each s),2.81 (2H, t), 3.31 (2H, t), 3.71 (2H, s), 6.60 (1H, s), 7.57 (2H, t),7.66 (2H, d).

Example 6(33){4-Methyl-2-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)thio]-1,3-thiazol-5-yl}aceticacid

Melting point 110-112° C.; ¹H-NMR (CDCl₃) δ 1.82-1.95 (2H, m) 2.24 (6H,s), 2.41-2.45 (2H, m), 3.07 (2H, t), 3.59 (2H, s) 6.53 (1H, s), 7.53(2H, d), 7.62 (2H, d).

Example 6(34)3-[6-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-2-naphthyl]propionicacid

Melting point 191-192° C.; ¹H-NMR (CDCl₃) δ 2.44 (3H, s) 2.76 (2H, t),3.09 (2H, t), 4.97 (2H, s), 6.82 (1H, s), 7.15-7.20 (2H, m), 7.31 (1H,dd) 7.57-7.60 (3H, m), 7.66-7.72 (4H, m).

Example 6(35)2-[(3-{2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]ethoxy}benzyl)thio]-2-methylpropionicacid

Melting point 78-81° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 3.31 (3H, s),2.82 (2H, t), 3.86 (2H, s), 4.07 (2H, t), 6.46 (1H, s), 6.76 (1H, dd),6.87 (1H, s), 6.90 (1H, d), 7.02 (2H, t), 7.18 (1H, t), 7.55 (2H, dd).

Example 6(36){4-Methyl-2-[({2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methyl)thio]-1,3-thiazol-5-yl}aceticacid

Melting point 163-165° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.31 (3H, s), 2.34(3H, s), 3,67 (2H, s), 4.15 (2H, s), 6.58 (1H, s), 7.18 (2H, d), 7.59(2H, d).

Example 6(37)2-{[3-({2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]pentyl}oxy)benzyl]thio}-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 0.90 (3H, t), 1.19-1.62 (3H, m), 1.56(6H, s), 1.71-1.88 (1H, m), 2.31 (3H, s), 2.89-3.00 (1H, m), 3.85 (2H,s), 3.95 (2H, d), 6.45 (1H, s), 6.73-6.77 (1H, m), 6.86 (1H, s), 6.89(1H, d), 7.03 (2H, t), 7.18 (1H, t), 7.57 (2H, dd).

Example 6(38)[2-({2-[5-(4-Fluorophenyl)-2-methyl-3-furyl]ethyl}thio)-4-methyl-1,3-thiazol-5-yl]aceticacid

Melting point 124-126° C.; ¹H-NMR (CDCl₃) δ 2.29 (3H, s) 2.32 (3H, s),2.80 (2H, t), 3.31 (2H, t), 3.72 (2H, s), 6.42 (1H, s), 7.03 (2H, t),7.55 (2H, dd).

Example 6(39)[5-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-2-methoxyphenyl]aceticacid

Melting point 138-139° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.95-2.05 (2H,m), 2.56 (2H, t), 2.64 (2H, q), 3.64 (2H, s), 3.79 (3H, s), 3.91 (2H,t), 6.59 (1H, s), 6.78 (3H, s), 7.57 (2H, d), 7.67 (2H, d).

Example 6(40)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-4-methoxyphenyl]aceticacid

Melting point 137-138° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 2.03-2.12 (2H,m), 2.58 (2H, t), 2.64 (2H, q), 3.55 (2H, s), 3.85 (3H, s), 4.01 (2H,t), 6.60 (1H, s), 6.78-6.82 (3H, m), 7.56 (2H, d), 7.66 (2H, d).

Example 6(41)2-[(3-{[5-(3-Methoxyphenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.56 (6H, s), 2.38 (3H, s), 3.84 (3H,s), 3.88 (2H, s), 4.83 (2H, s), 6.65 (1H, s), 6.77 (1H, ddd), 6.82-6.85(1H, m), 6.91-6.97 (2H, m), 7.15-7.28 (4H, m)

Example 6(42){[4-Fluoro-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 110-111° C.; ¹H-NMR (CDCl₃) δ 2.41 (3H, s) 3.08 (2H, s),3.80 (2H, s), 4.96 (2H, s), 6.80 (1H, s), 6.86-6.92 (1H, m), 6.99-7.08(2H, m), 7.59 (2H, d), 7.70 (2H, d).

Example 6(43){[2-Fluoro-5-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 105-106° C.; ¹H-NMR (CDCl₃) δ 2.40 (3H, s), 3.19 (2H, s),3.86 (2H, s), 4.84 (2H, s), 6.78 (1H, s), 6.82-6.88 (1H, m), 6.92-7.05(2H, m), 7.60 (2H, d), 7.71 (2H, d).

Example 6(44)2-[4-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]-2-methylpropionicacid

Melting point 102-103° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 1.58 (6H, s),1.97-2.06 (1H, m), 2.57 (2H, t), 2.64 (2H, q), 3.95 (2H, t), 6.59 (1H,s), 6.85 (2H, d), 7.30 (2H, d), 7.57 (2H, d), 7.66 (2H, d).

Example 6(45)2-[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]-2-methylpropionicacid

Melting point 94-95° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.58 (6H, s),1.98-2.07 (1H, m), 2.58 (2H, t), 2.64 (2H, q), 3.96 (2H, t), 6.59 (1H,s), 6.77 (1H, ddd), 6.94-6.98 (2H, m), 7.24 (1H, t), 7.57 (2H, d), 7.66(2H, d).

Example 6(46)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-4-fluorophenyl]aceticacid

Melting point 91-93° C.; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 2.01-2.10 (2H,m), 2.60 (2H, t), 2.64 (2H, q), 3.57 (2H, s), 4.02 (2H, t), 6.60 (1H,s), 6.78 (1H, ddd), 6.85 (1H, dd), 7.02 (1H, dd), 7.57 (2H, d), 7.67(2H, d).

Example 6(47)[5-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-2-fluorophenyl]aceticacid

Melting point 128-129° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.96-2.05 (2H,m), 2.57 (2H, t), 2.63 (2H, q), 3.67 (2H, d), 3.91 (2H, t), 6.58 (1H,s), 6.73-6.78 (2H, m), 6.97 (1H, t), 7.57 (2H, d), 7.67 (2H, d).

Example 6(48){[2-Methyl-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 151-152° C.; ¹H-NMR (CDCl₃) δ 2.27 (3H, s) 2.40 (3H, s),3.16 (2H, s), 3.88 (2H, s), 4.86 (2H, s), 6.78 (1H, s), 6.88 (1H, d),6.89 (1H, d), 7.12 (1H, t), 7.59 (2H, d), 7.71 (2H, d).

Example 6(49){[2-Ethoxy-5-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 85-87° C.; ¹H-NMR (CDCl₃) δ 1.41 (3H, t), 2.39 (3H, s),3.21 (2H, s), 3.84 (2H, s), 4.02 (2H, q), 4.82 (2H, s), 6.78 (1H, s),6.82 (1H, s), 6.82 (1H, d), 6.91 (1H, d), 7.58 (2H, d), 7.69 (2H, d).

Example 6(50)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-2-methylphenyl]aceticacid

Melting point 109-110° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 2.00-2.09 (2H,m), 2.22 (3H, s), 2.60 (2H, t), 2.63 (2H, q), 3.69 (2H, s), 3.96 (2H,t), 6.59 (1H, s), 6.75 (1H, d), 6.81 (1H, d), 7.10 (1H, t), 7.57 (2H,d), 7.66 (2H, d).

Example 6(51){[4-Methyl-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 120-121° C.; ¹H-NMR (CDCl₃) δ 2.21 (3H, s) 2.42 (3H, s),3.11 (2H, s), 3.83 (2H, s), 4.89 (2H, s), 6.78 (1H, s), 6.83 (1H, dd),6.91 (1H, d), 7.09 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 6(52)({1-[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]butyl}thio)aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 0.88 (3H, t), 1.21-1.42 (2H, m),1.77-1.91 (2H, m), 2.41 (3H, s), 2.93 (1H, d), 3.04 (1H, d), 3.97 (1H,dd), 4.87 (2H, s), 6.79 (1H, s), 6.85-6.95 (3H, m), 7.24 (1H, t), 7.59(2H, d), 7.70 (2H, d).

Example 6(53)[2-({[5-(3-Methoxyphenyl)-2-methyl-3-furyl]methyl}thio)-4-methyl-1,3-thiazol-5-yl]aceticacid

Melting point 174-176° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.31 (3H, s), 2.34(3H, s), 3.67 (2H, s), 3.84 (3H, s), 4.15 (2H, s), 6.60 (1H, s),6.75-6.79 (1H, m), 7.13 (1H, s), 7.18 (1H, d), 7.26 (1H, t).

Example 6(54){[4-Chloro-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 99-101° C.; ¹H-NMR (CDCl₃) δ 2.43 (3H, s), 3.08 (2H, s),3.82 (2H, s), 4.98 (2H, s), 6.82 (1H, s), 6.89 (1H, dd), 7.03 (1H, d),7.32 (1H, d), 7.60 (2H, d), 7.71 (2H, d).

Example 6(55){[3-Methyl-5-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}aceticacid

Melting point 123-124° C.; ¹H-NMR (CDCl₃) δ 2.32 (3H, s) 2.41 (3H, s),3.13 (2H, s), 3.79 (2H, s), 4.85 (2H, s), 6.70 (1H, s), 6.76 (2H, s),6.77 (1H, s), 7.58 (2H, d), 7.69 (2H, d).

Example 6(56)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-5-methylphenyl]aceticacid

Melting point 100-101° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t) 1.96-2.04 (2H,m), 2.30 (3H, s), 2.57 (2H, t), 2.64 (2H, q), 3.56 (2H, s), 3.94 (2H,t), 6.59 (1H, s), 6.63 (2H, s), 6.67 (1H, s), 7.56 (2H, d), 7.66 (2H,d).

Example 6(57)2-[4-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenoxy]-2-methylpropionicacid

Melting point 70-71° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.53 (6H, s),1.95-2.09 (2H, m), 2.58 (2H, t), 2.64 (2H, q), 3.93 (2H, t), 6.60 (1H,s), 6.81 (2H, d), 6.92 (2H, d), 7.58 (2H, d), 7.68 (2H, d).

Example 6(58)2-[2-Chloro-4-(3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenoxy]-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.58 (6H, s), 1.97-2.06(2H, m), 2.57 (2H, t), 2.63 (2H, q), 3.92 (2H, t), 6.58 (1H, s), 6.73(1H, dd), 6.94 (1H, d), 7.04 (1H, d), 7.57 (2H, d), 7.67 (2H, d).

Example 6(59)2-Methyl-2-{[3-({2-methyl-5-[3-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}propionicacid

Melting point 81-82° C.; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.40 (3H, s),3.88 (2H, s), 4.86 (2H, s), 6.75 (1H, s), 6.82-6.87 (1H, m), 6.92-6.96(2H, m), 7.22 (1H, t), 7.46 (2H, d), 7.75-7.79 (1H, m), 7.86 (1H, s).

Example 6(60)2-(4-{[5-(3-Methoxyphenyl)-2-methyl-3-furyl]methoxy}phenoxy)-2-methylpropionicacid

Melting point 111-112° C.; ¹H-NMR (CDCl₃) δ 1.54 (6H, s), 2.38 (3H, s),3.84 (3H, s), 4.82 (2H, s), 6.64 (1H, s), 6.76-6.80 (1H, m), 6.88 (2H,d), 6.93 (2H, d), 7.15-7.29 (3H, m).

Example 6(61)(3-{3-[2-Ethyl-5-(3-methoxyphenyl)-3-furyl]propoxy}phenyl)acetic acid

An oily matter; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 1.96-2.05 (2H, m), 2.56(2H, t), 2.62 (2H, q), 3.61 (2H, s), 3.84 (3H, s), 3.95 (2H, t), 6.47(1H, s), 6.73-6.76 (1H, m), 6.79-6.86 (3H, m), 7.13-7.27 (4H, m).

Example 6(62)2-(4-{3-[2-Ethyl-5-(3-methoxyphenyl)-3-furyl]propoxy}phenoxy)-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.20 (3H, t), 1.53 (6H, s), 1.96-2.05(2H, m), 2.56 (2H, t), 2.61 (2H, q), 3.84 (3H, s), 3.92 (2H, t), 6.46(1H, s), 6.72-6.77 (1H, m), 6.79 (2H, d), 6.90 (2H, d), 7.12-7.27 (3H,m).

Example 6(63)2-Methyl-2-[4-({2-methyl-5-[3-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propionicacid

Melting point 83-84° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 2.40 (3H, s),4.84 (2H, s), 6.75 (1H, s), 6.86-6.97 (4H, m), 7.47 (2H, d), 7.75-7.79(1H, m), 7.86 (1H, s).

Example 6(64){4-Methyl-2-[({2-methyl-5-[3-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-1,3-thiazol-5-yl}aceticacid

Melting point 193-194° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.33 (3H, s), 2.34(3H, s), 3.67 (2H, s), 4.16 (2H, s), 6.70 (1H, s), 7.45-7.48 (2H, m),7.72-7.77 (1H, m), 7.83 (1H, s).

Example 6(65)2-{[1-(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}phenyl)ethyl]thio}-2-methylpropionicacid

Melting point 89-90° C.; ¹H-NMR (CDCl₃) δ 1.39 (3H, s), 1.53 (3H, s),1.56 (3H, d), 2.38 (3H, s), 4.13 (1H, q), 4.85 (2H, s), 6.59 (1H, s),6.81 (1H, dd), 6.93 (1H, d), 6.97 (1H, t), 7.04 (2H, t), 7.20 (1H, t),7.57 (2H, dd).

Example 6(66)2-Methyl-2-({1-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]ethyl}thio)propionicacid

Melting point 75-77° C.; ¹H-NMR (CDCl₃) δ 1.40 (3H, s), 1.53 (3H, s),1.56 (3H, d), 2.42 (3H, s), 4.14 (1H, q), 4.87 (2H, s), 6.79 (1H, s),6.79-6.84 (1H, m), 6.92-6.99 (2H, m), 7.21 (1H, t), 7.59 (2H, d), 7.71(2H, d).

Example 6(67)2-[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]propionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.50 (3H, d) 1.97-2.06(2H, m), 2.58 (2H, t), 2.64 (2H, q), 3.71 (1H, q), 3.96 (2H, t), 6.59(1H, s), 6.79 (1H, ddd), 6.86-6.91 (2H, m), 7.23 (1H, t), 7.56 (2H, d),7.66 (2H, d).

Example 6(68)2-[2-Fluoro-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]-2-methylpropionicacid

Melting point 82-83° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, d), 2.41 (3H, s),4.83 (2H, s), 6.65-6.80 (2H, m), 6.77 (1H, s), 7.05 (1H, t), 7.60 (2H,d), 7.71 (2H, d).

Example 6(69)2-[4-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-2-fluorophenoxy]-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 1.54 (6H, s) 1.95-2.09(2H, m), 2.54-2.69 (4H, m), 3.92 (2H, t), 6.56-6.71 (2H, m), 6.59 (1H,s), 7.03 (1H, t), 7.58 (2H, d), 7.68 (2H, d).

Example 6(70)2-Methyl-2-{[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]oxy}propionicacid

Melting point 95-96° C.; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.42 (3H, s),4.52 (2H, s), 4.89 (2H, s), 6.79 (1H, s), 6.89-7.01 (3H, m), 7.30 (1H,t), 7.60 (2H, d), 7.71 (2H, d).

Example 6(71)2-[(3-{[5-(4-Fluorophenyl)-2-methyl-3-furyl]methoxy}benzyl)oxy]-2-methylpropionicacid

Amorphous powders; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.39 (3H, s), 4.52(2H, s), 4.87 (2H, s), 6.60 (1H, s), 6.90-7.09 (5H, m), 7.29 (1H, t),7.59 (2H, dd).

Example 6(72){2-[({2-(Ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-4-methyl-1,3-thiazol-5-yl}aceticacid

Melting point 104-106° C.; ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 2.34 (3H, s),3.56 (2H, q), 3.73 (2H, s), 4.26 (2H, s), 4.51 (2H, s), 6.75 (1H, s),7.59 (2H, d), 7.72 (2H, d).

Example 6(73){2-[({2-Butyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-4-methyl-1,3-thiazol-5-yl}aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 0.92 (3H, t), 1.32-1.39 (2H, m),1.59-1.66 (2H, m), 2.30 (3H, s), 2.62 (2H, t), 2.80 (2H, t), 3.28 (2H,t), 3.67 (2H, s), 6.60 (1H, s), 7.56 (2H, d), 7.65 (2H, d).

Example 6(74)2-{[3-({2-(Ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}-2-methylpropionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 1.55 (6H, s) 3.60 (2H,q), 3.88 (2H, s), 4.58 (2H, s), 4.97 (2H, s), 6.83-6.87 (2H, m),6.92-6.98 (2H, m), 7.19 (1H, d), 7.60 (2H, d), 7.75 (2H, d).

Example 6(75)2-[2-Methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]butanoicacid

Melting point 118-119° C.; ¹H-NMR (CDCl₃) δ 0.97 (3H, t), 1.58-1.72 (2H,m), 2.30 (3H, s), 2.39 (3H, s), 2.54-2.58 (1H, m), 2.72 (1H, dd), 2.92(1H, dd), 4.82 (2H, s), 6.71-6.79 (3H, m), 7.06 (1H, d), 7.58 (2H, d),7.70 (2H, d).

Example 6(76)2-Methyl-3-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 96-97° C.; ¹H-NMR (CDCl₃) δ 1.20 (3H, d), 2.30 (3H, s),2.39 (3H, s), 2.57-2.75 (2H, m), 3.04 (1H, dd), 4.82 (2H, s), 6.72-6.78(3H, m), 7.04 (1H, d), 7.57 (2H, d), 7.69 (2H, d).

Example 6(77)2-Methoxy-3-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 125-126° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s) 2.40 (3H, s),2.97 (1H, dd), 3.13 (1H, dd), 3.35 (3H, s), 3.95 (1H, dd), 4.83 (2H, s),6.74-6.79 (3H, m), 7.12 (1H, d), 7.58 (2H, d), 7.69 (2H, d).

Example 6(78)2,2-Dimethyl-3-[4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 125-127° C.; ¹H-NMR (CDCl₃) δ 1.20 (6H, s) 2.38 (3H, s),2.48 (2H, s), 4.82 (2H, s), 6.75 (1H, s), 6.88 (2H, d), 7.10 (2H, d),7.57 (2H, d), 7.68 (2H, d).

Example 6(79)2,2-Dimethyl-3-[4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)phenyl]propionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.18 (6H, s), 2.33 (3H, s) 2.78-2.86(4H, m), 4.06 (2H, t), 6.65 (1H, s), 6.81 (2H, d), 7.07 (2H, d), 7.56(2H, d), 7.66 (2H, d).

Example 6(80)2,2-Dimethyl-3-[4-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]propionicacid

Amorphous powders; ¹H-NMR (CDCl₃) δ 1.18 (6H, s), 2.00 (2H, t), 2.26(3H, s), 2.56 (2H, t), 2.82 (2H, s), 3.93 (2H, t), 6.59 (1H, s), 6.80(2H, d), 7.07 (2H, d), 7.56 (2H, d), 7.65 (2H, d)

Example 6(81)[3-Methoxy-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]aceticacid

Melting point 139-140° C.; ¹H-NMR (CDCl₃) δ 2.38 (3H, s) 3.59 (2H, s),3.86 (3H, s), 4.91 (2H, s), 6.78-6.82 (3H, m), 7.58 (2H, d), 7.69 (2H,d).

Example 6(82)3-[4-Methoxy-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 128-129° C.; ¹H-NMR (CDCl₃) δ 2.38 (3H, s) 2.60-2.68 (2H,m), 2.89 (2H, t), 3.84 (3H, s), 4.91 (2H, s), 6.81 (4H, s), 7.58 (2H,d), 7.69 (2H, d).

Example 6(83)[3-(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethoxy)phenyl]aceticacid

Melting point 92-94° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 2.84 (2H, t),3.61 (2H, s), 4.08 (2H, t), 6.66 (1H, s), 6.81-6.88 (3H, m), 7.19-7.27(1H, m), 7.57 (2H, d), 7.68 (2H, d).

Example 6(84)[3-(3-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 111-113° C.; ¹H-NMR (CDCl₃) δ 2.01 (2H, t), 2.26 (3H, s),2.56 (2H, t), 3.61 (2H, s), 3.95 (2H, t), 6.59 (1H, s), 6.80-6.87 (3H,m), 7.19-7.27 (1H, m), 7.56 (2H, d), 7.66 (2H, d).

Example 6(85)2-Methyl-2-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 127-128° C.; ¹H-NMR (CDCl₃) δ 1.59 (6H, s), 2.40 (3H, s),4.85 (2H, s), 6.78 (1H, s), 6.85-6.89 (1H, m), 7.00-7.02 (2H, m),7.24-7.30 (1H, m), 7.59 (2H, d), 7.70 (2H, d).

Example 6(86)2-Methyl-2-[4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 105-107° C.; ¹H-NMR (CDCl₃) δ 1.58 (6H, s), 2.39 (3H, s),4.85 (2H, s), 6.76 (1H, s), 6.94 (2H, d), 7.34 (2H, d), 7.59 (2H, d),7.70 (2H, d).

Example 6(87)[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

Melting point 118-119° C.; ¹H-NMR (CDCl₃) δ 2.40 (3H, s), 4.66 (2H, s),4.84 (2H, s), 6.51-6.54 (1H, m), 6.56-6.58 (1H, m), 6.62-6.66 (1H, m),6.77 (1H, s), 7.11 (1H, d), 7.59 (2H, d), 7.69 (2H, d).

Example 6(88)2-Methyl-2-{[4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]thio}propionicacid

Melting point 128-129° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.38 (3H, s),4.84 (2H, s), 6.73 (1H, s), 6.93 (2H, d), 7.46 (2H, d), 7.58 (2H, d),7.68 (2H, d).

Example 6(89)3-[5-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1-benzofuran-2-yl]propionicacid

Melting point 156-157° C.; ¹H-NMR (CDCl₃) δ 2.39 (3H, s), 2.82 (2H, t),3.10 (2H, t), 4.88 (2H, s), 6.39 (1H, s), 6.80 (1H, s), 6.88 (1H, dd),7.04 (1H, d), 7.30 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 6(90)[5-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1-benzofuran-2-yl]aceticacid

Melting point 140-142° C.; ¹H-NMR (CDCl₃) δ 2.34 (3H, s), 3.75 (2H, s),4.80 (2H, s), 6.51 (1H, s), 6.74 (1H, s), 6.86 (1H, d), 7.00 (1H, s),7.25 (1H, s), 7.55 (2H, d), 7.65 (2H, d).

Example 6(91)3-[4-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-2-propylphenyl]propionicacid

Melting point 129-131° C.; ¹H-NMR (CDCl₃) δ 0.99 (3H, t), 1.57-1.68 (2H,m), 2.40 (3H, s), 2.54-2.66 (4H, m), 2.93 (2H, t), 4.84 (2H, s),6.73-6.79 (3H, m), 7.09 (1H, d), 7.59 (2H, d), 7.70 (2H, d).

Example 6(92)2-[2-Chloro-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]-2-methylpropionicacid

Melting point 92-93° C.; ¹H-NMR (CDCl₃) δ 1.59 (6H, s), 2.40 (3H, s),4.82 (2H, s), 6.75 (1H, s), 6.81 (1H, dd), 7.02 (1H, d), 7.07 (1H, d),7.59 (2H, d), 7.70 (2H, d).

Example 6(93)[3-Chloro-4-(3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 112-113° C.; ¹H-NMR (CDCl₃) δ 1.20 (3H, t), 2.04-2.08 (2H,m), 2.64-2.68 (4H, m), 3.57 (2H, s), 4.00 (2H, t), 6.59 (1H, s), 6.82(1H, d), 7.08 (1H, dd), 7.30 (1H, d), 7.57 (2H, d), 7.66 (2H, d).

Example 6(94)2-{[4-Fluoro-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}-2-methylpropionicacid

Melting point 120-123° C.; ¹H-NMR (CDCl₃) δ 1.54 (6H, s), 2.40 (3H, s),3.83 (2H, s), 4.93 (2H, s), 6.78 (1H, s), 6.88-6.89 (1H, m), 6.93-7.06(2H, m), 7.58 (2H, d), 7.68 (2H, d).

Example 6(95)2-{[2-Fluoro-5-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}-2-methylpropionicacid

Melting point 131-132° C.; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.39 (3H, s),3.90 (2H, s), 4.81 (2H, s), 6.76-6.82 (2H, m), 6.90-6.99 (2H, m), 7.58(2H, d), 7.69 (2H, d).

Example 6(96)2-{[2-Fluoro-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}-2-methylpropionicacid

Melting point 106-108° C.; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.38 (3H, s),3.93 (2H, s), 4.91 (2H, s), 6.77 (1H, s), 6.90-6.99 (3H, m), 7.58 (2H,d), 7.68 (2H, d).

Example 6(97)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-2-fluorophenyl]aceticacid

Melting point 92-93° C.; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 1.98-2.12 (2H,m), 2.57-2.70 (4H, m), 3.72 (2H, d), 4.02 (2H, t), 6.60 (1H, s),6.78-7.04 (3H, m), 7.57 (2H, d), 7.67 (2H, d).

Example 6(98)[4-Chloro-3-(3-{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]aceticacid

Melting point 104-105° C.; ¹H-NMR (CDCl₃) δ 1.20 (3H, t), 2.03-2.10 (2H,m), 2.59-2.70 (4H, m), 3.58 (2H, s), 4.02 (2H, t), 6.60 (1H, s),6.78-6.81 (2H, m), 7.31 (1H, d), 7.57 (2H, d), 7.67 (2H, d).

Example 6(99)2-{[4-Chloro-3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}-2-methylpropionicacid

Melting point 140-142° C.; ¹H-NMR (CDCl₃) δ 1.53 (6H, s), 2.41 (3H, s),3.84 (2H, s), 4.93 (2H, s), 6.79 (1H, s), 6.86 (1H, dd), 6.99 (1H, d),7.24 (1H, s), 7.58 (2H, d), 7.69 (2H, d).

Example 6(100)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-1H-indazol-1-yl]aceticacid

Melting point 139-140° C.; ¹H-NMR (CDCl₃) δ 1.22 (3H, t), 2.07-2.12 (2H,m), 2.57-2.68 (4H, m), 4.37 (2H, t), 4.92 (2H, s), 6.61 (1H, s),7.06-7.11 (1H, m), 7.16 (1H, d), 7.37-7.42 (1H, m), 7.56 (2H, d),7.64-7.69 (3H, m).

Example 6(101)[5-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1-benzothien-2-yl]aceticacid

Melting point 153-154° C.; ¹H-NMR (CDCl₃) δ 2.41 (3H, s), 3.94 (2H, d),4.91 (2H, s), 6.79 (1H, s), 7.00 (1H, dd), 7.12 (1H, s), 7.24-7.25 (1H,m), 7.59 (2H, d), 7.65 (1H, d), 7.70 (2H, d).

Example 6(102)[5-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)-1-benzothien-2-yl]aceticacid

Melting point 111-112° C.; ¹H-NMR (CDCl₃) δ 1.21 (3H, t), 2.04 (2H, t),2.57-2.67 (4H, m), 3.92 (2H, s), 3.99 (2H, t), 6.59 (1H, s), 6.93-6.96(1H, m), 7.08 (1H, s), 7.13 (1H, s), 7.55 (2H, d), 7.60 (1H, s), 7.66(2H, d).

Example 6(103)3-[5-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1-benzothien-2-yl]propionicacid

Melting point 187-188° C.; ¹H-NMR (CDCl₃) δ 2.41 (3H, s), 2.73 (2H, t),3.21 (2H, t), 4.91 (2H, s), 6.81 (1H, s), 6.93-6.98 (2H, m), 7.21 (1H,d), 7.59 (2H, d), 7.62 (1H, s), 7.71 (2H, d).

Example 6(104)2-Methyl-2-[4-(4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butoxy)phenoxy]propionicacid

Melting point 67-69° C.; ¹H-NMR (CDCl₃) δ 1.53 (6H, s), 1.70-1.83 (4H,m), 2.29 (3H, s), 2.38-2.45 (2H, m), 3.93 (2H, t), 6.58 (1H, s), 6.79(2H, d), 6.90 (2H, d), 7.56 (2H, d), 7.66 (2H, d).

Example 6(105)2-Methyl-2-{4-[((E)-4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-butenyl)oxy]phenoxy}propionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.54 (6H, s), 2.37 (3H, s), 2.63-2.69(2H, m), 4.02 (2H, t), 5.97 (1H, dt), 6.30 (1H, d), 6.81-6.87 (3H, m),6.88-6.95 (2H, m), 7.58 (2H, d), 7.69 (2H, d).

Example 6(106)2-Methyl-2-{[4-(4-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}butoxy)phenyl]thio}propionicacid

Melting point 155-156° C.; ¹H-NMR (CDCl₃) δ 1.46 (6H, s), 1.68-1.83 (4H,m), 2.29 (3H, m), 2.36-2.44 (2H, m), 3.95 (2H, t), 6.58 (1H, s), 6.82(2H, d), 7.40 (2H, d), 7.56 (2H, d), 7.66 (2H, d).

Example 6(107)2-Methyl-2-({[5-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1-benzothien-2-yl]methyl}thio)propionicacid

Melting point 158-159° C.; ¹H-NMR (CDCl₃) δ 1.57 (6H, s), 2.40 (3H, s),4.16 (2H, d), 4.89 (2H, s), 6.78 (1H, s), 6.98 (1H, dd), 7.12 (1H, s),7.21 (1H, d), 7.59 (2H, d), 7.62 (1H, d), 7.70 (2H, d).

Example 6(108)2-Methyl-2-{[4-({2-methyl-5-[3-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]thio}propionicacid

Melting point 108-109° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.38 (3H, s),4.85 (2H, s), 6.71 (1H, s), 6.94 (2H, d), 7.44-7.48 (4H, m), 7.72-7.76(1H, m), 7.84 (1H, s).

Example 6(109)2-Methyl-2-{[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}propionicacid

Melting point 148-149° C.; ¹H-NMR (CDCl₃) δ 1.56 (6H, s), 2.40 (3H, s),3.88 (2H, s), 4.85 (2H, s), 6.77 (1H, s), 6.81-6.97 (3H, m), 7.20 (1H,d), 7.59 (2H, d), 7.70 (2H, d).

Example 6(110)2-[(3-{[5-(4-Methoxyphenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]-2-methylpropionicacid

Melting point 96-97° C.; ¹H-NMR (CDCl₃) δ 1.56 (6H, s), 2.36 (3H, s),3.82 (3H, s), 3.87 (2H, s), 4.83 (2H, s), 6.52 (1H, s), 6.81-6.97 (4H,m), 7.19 (1H, d), 7.55 (2H, d).

Example 6(111)2-[(3-{[5-(4-Chlorophenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]-2-methylpropionicacid

Melting point 143-144° C.; ¹H-NMR (CDCl₃) δ 1.56 (6H, s), 2.37 (3H, s),3.87 (2H, s), 4.83 (2H, s), 6.64 (1H, s), 6.80-6.95 (3H, m), 7.19 (1H,d), 7.31 (2H, d), 7.54 (2H, d).

Example 6(112)2-[(3-{[5-(3-Fluorophenyl)-2-methyl-3-furyl]methoxy}benzyl)thio]-2-methylpropionicacid

Melting point 116-117° C.; ¹H-NMR (CDCl₃) δ 1.56 (6H, s) 2.38 (3H, s),3.88 (2H, s), 4.84 (2H, s), 6.68 (1H, s), 6.82-6.97 (4H, m), 7.18-7.39(4H, m).

Example 6(113)2-[(4-{[5-(4-Methoxyphenyl)-2-methyl-3-furyl]methoxy}phenyl)thio]-2-methylpropionicacid

Melting point 145-146° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.34 (3H, s),3.81 (3H, s), 4.82 (2H, s), 6.48 (1H, s), 6.86-6.95 (4H, m), 7.45 (2H,d), 7.53 (2H, d).

Example 6(114)2-[(4-{[5-(4-Chlorophenyl)-2-methyl-3-furyl]methoxy}phenyl)thio]-2-methylpropionicacid

Melting point 130-131° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.36 (3H, s),4.83 (2H, s), 6.61 (1H, s), 6.93 (2H, d), 7.31 (2H, d), 7.46 (2H, d),7.53 (2H, d).

Example 6(115)2-[(4-{[5-(3-Fluorophenyl)-2-methyl-3-furyl]methoxy}phenyl)thio]-2-methylpropionicacid

Melting point 146-147° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.37 (3H, s),4.84 (2H, s), 6.65 (1H, s), 6.92-6.95 (3H, m), 7.26-7.38 (3H, m), 7.46(2H, d).

Example 6(116)2-Methyl-2-{[3-({2-methyl-5-[2-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}propionicacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 2.38 (3H, s), 3.86 (2H,s), 4.85 (2H, s), 6.71 (1H, s), 6.79-6.96 (3H, m), 7.16-7.24 (1H, m),7.36 (1H, t), 7.53 (1H, t), 7.69-7.74 (2H, m).

Example 6(117)2-Methyl-2-{[4-({2-methyl-5-[2-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]thio}propionicacid

Melting point 115-116° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 2.37 (3H, s),4.86 (2H, s), 6.70 (1H, s), 6.93 (2H, d), 7.36-7.39 (1H, m), 7.45 (2H,d), 7.53 (1H, t), 7.70-7.73 (2H, m).

Example 6(118)2-Methyl-2-{[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]thio}propionicacid

Melting point 127-128° C.; ¹H-NMR (CDCl₃) δ 1.49 (6H, s), 2.38 (3H, s),4.83 (2H, s), 6.75 (1H, s), 6.95-6.99 (1H, m), 7.10-7.13 (2H, m),7.21-7.27 (1H, m), 7.58 (2H, d), 7.68 (2H, d).

Example 6(119)2-Methyl-2-({3-[(2-methyl-5-phenyl-3-furyl)methoxy]benzyl}thio)propionicacid

Melting point 113-114° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 2.37 (3H, s),3.87 (2H, s), 4.84 (2H, s), 6.64 (1H, s), 6.81-6.85 (1H, m), 6.91-6.97(2H, m), 7.17-7.24 (2H, m), 7.33-7.36 (2H, m), 7.59-7.62 (2H, m).

Example 6(120)2-Methyl-2-[(3-{[2-methyl-5-(4-methylphenyl)-3-furyl]methoxy}benzyl)thio]propionicacid

Melting point 121-122° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 2.34 (3H, s),2.36 (3H, s), 3.87 (2H, s), 4.83 (2H, s), 6.58 (1H, s), 6.81-6.85 (1H,m), 6.90-6.96 (2H, m), 7.13-7.24 (3H, m), 7.50 (2H, d).

Example 6(121)[3-(3-{2-Ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methoxypropoxy)phenyl]aceticacid

An oily matter; ¹H-NMR (CDCl₃) δ 1.23 (3H, t), 2.00-2.06 (1H, m),2.32-2.38 (1H, m), 2.64-2.73 (2H, m), 3.23 (3H, s), 3.60 (2H, s),3.88-3.93 (1H, m), 4.06-4.13 (1H, m), 4.43 (1H, t), 6.69 (1H, s),6.77-6.87 (3H, m), 7.19-7.25 (1H, m), 7.60 (2H, d), 7.70 (2H, d).

Example 6(122)2-Methyl-2-{[4-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propoxy)phenyl]thio}propionicacid

Melting point 127-128° C.; ¹H-NMR (CDCl₃) δ 1.48 (6H, s), 1.98-2.05 (2H,m), 2.26 (3H, s), 2.57 (2H, t), 3.95 (2H, t), 6.58 (1H, s), 6.85 (2H,d), 7.43 (2H, d), 7.57 (2H, d), 7.67 (2H, d).

Example 6(123)3-[4-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenyl]propionicacid

Melting point 182-183° C.; ¹H-NMR (CDCl₃) δ 2.40 (3H, s), 2.66 (2H, t),2.92 (2H, t), 4.85 (2H, s), 6.78 (1H, s), 6.91 (2H, d), 7.15 (2H, d),7.60 (2H, d), 7.71 (2H, d).

Example 6(124)N-methyl-N-[3-({2-methyl-5-[4-(trifluoromethyl)-phenyl]-3-furyl}methoxy)benzyl]glycine

Amorphous; ¹H-NMR (DMSO-d₆) δ 2.34 (3H, s), 2.42 (3H, s), 3.19 (2H, s),3.75 (2H, s), 4.94 (2H, s), 6.93-6.97 (2H, m), 7.04 (1H, s), 7.20 (1H,s), 7.28 (1H, t), 7.74 (2H, d), 7.86 (2H, d).

Example 6(125)3′-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1,1′-biphenyl-3-carboxylicacid

Melting point 178-179° C.; ¹H-NMR (CDCl₃) δ 2.44 (3H, s), 4.96 (2H, s),6.82 (1H, s), 6.99-7.03 (1H, m), 7.24-7.27 (2H, m), 7.41 (1H, t),7.52-7.61 (3H, m), 7.72 (2H, d), 7.82-7.85 (1H, m), 8.08-8.12 (1H, m),8.34-8.36 (1H, m).

Example 6(126)[3′-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-1,1′-biphenyl-3-yl]aceticacid

Melting point 128-129° C.; ¹H-NMR (CDCl₃) δ 2.41 (3H, s), 3.70 (2H, s),4.92 (2H, s), 6.81 (1H, s), 6.93-6.99 (1H, m), 7.18-7.43 (5H, m),7.48-7.52 (2H, m), 7.59 (2H, d), 7.71 (2H, d).

Example 7 Ethyl3-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)phenyl]propionate

To a suspension (5 ml) of 3 sodium hydride (81 mg) in tetrahydrofuranwas added dropwise ethyl diethylphosphonoacetate (0.26 ml) withice-cooling and the mixture was stirred for 30 minutes. To the reactionsolution was added dropwise a solution ofN-(3-formylphenyl)-2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furamide(0.50 g) in tetrahydrofuran (5 ml) and the mixture was stirred at 0° C.for 2 hours. 1 N hydrochloric acid was added thereto and the mixture wasdiluted with ethyl acetate. The organic layer was separated and washedwith a saturated sodium bicarbonate solution, water and saturated brine.The organic layer was dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The obtained residue wasdissolved in a solution of ethanol-tetrahydrofuran (5 ml-5 ml) and 10%palladium-carbon was added thereto under nitrogen gas stream, theatmosphere was substituted with a hydrogen atmosphere and the mixturewas stirred at room temperature for 3 hours. Insolubles were filteredand purified by silica gel column chromatography (hexane:ethylacetate=8:1 to 5:1) to obtain an objective product (0.38 g) as crystals.

Melting point 134-135° C.; ¹H-NMR (CDCl₃) δ 1.24 (3H, t), 2.63 (2H, t),2.72 (3H, s), 2.96 (2H, t), 4.13 (2H, q), 6.89 (1H, s), 6.99 (1H, d),7.23-7.31 (1H, m), 7.41-7.50 (3H, m), 7.64 (2H, d), 7.75 (2H, d).

Example 83-[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)phenyl]propionicacid

To a solution of ethyl3-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoyl}amino)phenyl]propionate(0.33 g) in tetrahydrofuran-ethanol (3 ml-3 ml) was added dropwise a 1 Naqueous sodium hydroxide solution (1.5 ml) and the mixture was stirredat room temperature for 1 hour. The mixture was acidified with 1 Nhydrochloric acid and diluted with ethyl acetate. The organic layer wasseparated and washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The obtained residue was purified by recrystallization(hexane-ethyl acetate) to obtain an objective product (245 mg) ascrystals.

Melting point 200-201° C.; ¹H-NMR (CDCl₃) δ 2.62 (2H, t), 2.73 (3H, s),2.95 (2H, t), 6.97 (1H, d), 7.24 (1H, t), 7.34 (1H, s), 7.54-7.59 (2H,m), 7.64 (2H, d), 7.77 (2H, d), 9.01 (1H, s).

Example 92-{[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}butanoicacid

To a solution ofS-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thioacetate(0.50 g) in methanol (10 ml) was added a 1 N aqueous sodium hydroxidesolution (1.2 ml) at room temperature and the mixture was stirred assuch for 1 hour. The solvent of the mixture was distilled off underreduced pressure to obtain a solid matter. The obtained solid matter wasdissolved in N,N-dimethylformamide (10 ml), and ethyl 2-bromobutyrate(0.28 g) was added thereto at room temperature. The mixture was stirredat 60° C. overnight. The reaction solution was poured into water andtwice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=15:1 to 9:1) toobtain an oily matter.

The obtained oily matter was dissolved in methanol (5 ml) andtetrahydrofuran (5 ml), a 1 N aqueous sodium hydroxide solution (3 ml)was added thereto and the mixture was stirred at room temperatureovernight. The reaction solution was concentrated and diluted withwater. The reaction solution was acidified with dilute hydrochloric acidand twice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous sodium sulfate and passed through silica gel. Theobtained crude product was crystallized from diethyl ether-hexane toobtain an objective product (0.24) as crystals.

Melting point 78-80° C.; ¹H-NMR (CDCl₃) δ 0.96 (3H, t), 1.59-1.95 (2H,m), 2.42 (3H, s), 3.10 (1H, t), 3.79 (1H, d), 3.88 (1H, d), 4.88 (2H,s), 6.80 (1H, s), 6.85-6.98 (3H, m), 7.25 (1H, t), 7.60 (2H, d), 7.71(2H, d).

Example 9(1) to Example 9(4)

In the same manner as in Example 9,S-[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thioacetatewas condensed with the corresponding α-haloester and hydrolyzed toobtain the below-described compounds.

Example 9(1)2-{[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-benzyl]thio}propionicacid

Melting point 82-83° C.; ¹H-NMR (CDCl₃) δ 1.40 (3H, d), 2.41 (3H, s),3.31 (1H, q), 3.80 (1H, d), 3.90 (1H, d), 4.87 (2H, s), 6.79 (1H, s),6.85-6.89 (1H, m), 6.95-6.99 (2H, m), 7.24 (1H, t), 7.59 (2H, d), 7.70(2H, d).

Example 9(2)Difluoro{[3-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)-benzyl]thio}aceticacid

Amorphous powders; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.36 (3H, s), 4.02 (2H, s),4.80 (2H, s), 6.74 (1H, s), 6.80 (1H, dd), 6.90 (1H, d), 6.95 (1H, s),7.16 (1H, t), 7.56 (2H, d), 7.66 (2H, d).

Example 9(3)1-{[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}cyclobutanecarboxylicacid

Melting point 121-122° C.; ¹H-NMR (CDCl₃) δ 1.87-1.99 (1H, m), 2.11-2.25(3H, m), 2.41 (3H, s), 2.63-2.73 (2H, m), 3.78 (2H, s), 4.86 (2H, s),6.78 (1H, s), 6.83-6.86 (1H, m), 6.92-6.96 (2H, m), 7.22 (1H, t), 7.58(2H, d), 7.69 (2H, d).

Example 9(4)2-{[3-({2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)benzyl]thio}pentanoicacid

Melting point 61-62° C.; ¹H-NMR (CDCl₃) δ 0.83 (3H, t), 1.26-1.45 (2H,m), 1.55-1.66 (1H, m), 1.76-1.88 (1H, m), 2.41 (3H, s), 3.18 (1H, t),3.80 (1H, d), 3.87 (1H, d), 4.88 (2H, s), 6.79 (1H, s), 6.87 (1H, dd),6.97 (1H, d), 6.99 (1H, s), 7.25 (1H, t), 7.60 (2H, d), 7.71 (2H, d).

Example 10{2-[(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-2-oxoethyl)thio]-4-methyl-1,3-thiazol-5-yl}aceticacid

To a solution of1-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethanone (0.48 g), 47%hydrobromic acid (1 drop) and acetic acid (2 ml) in diethyl ether (20ml) was added at 0° C. a solution of bromine (91 μl) in diethyl ether (5ml) and the mixture was stirred as such for 15 minutes. The reactionsolution was diluted with ethyl acetate, washed with water, dried overanhydrous sodium sulfate and the solvent was distilled off under reducedpressure to obtain a solid matter. To a solution of methyl(2-mercapto-4-methyl-1,3-thiazol-5-yl)acetate (0.43 g) intetrahydrofuran (2 ml) was added 1,8-diazabicyclo[5.4.0]-7-undecene(0.32 ml) at room temperature and the mixture was stirred for 10minutes. The obtained mixture was added to a solution of the obtainedsolid matter in tetrahydrofuran (20 ml) at room temperature and themixture was stirred as such overnight. The reaction solution was pouredinto water and twice extracted with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=3:1to 1:1) to obtain a solid matter.

The obtained solid matter was dissolved in methanol (5 ml) andtetrahydrofuran (5 ml), a 1 N aqueous sodium hydroxide solution (2 ml)was added thereto, and then the mixture was stirred at room temperatureovernight. The reaction solution was concentrated and diluted withwater. The reaction solution was acidified with dilute hydrochloric acidand twice extracted with ethyl acetate. The collected organic layer wasdried over anhydrous sodium sulfate and the solvent was distilled offunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1 to ethylacetate) and crystallized from hexane to obtain an objective product (54mg) as powders.

Melting point 140-143° C.; ¹H-NMR (CDCl₃-DMSO-d₆) δ 2.31 (3H, s), 2.70(3H, s), 3.66 (2H, s), 4.46 (2H, s), 7.10 (1H, s), 7.64 (2H, d), 7.75(2H, d).

Example 11 Ethyl[2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]acetate

To a solution of ethyl4-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]-3-oxobutanoate(0.46 g) in tetrahydrofuran (10 ml) was added Lawson's reagent (0.66 g)and the mixture was stirred at 70° C. for 1 hour. The solvent wasdistilled off under reduced pressure and the obtained crude product waspurified by silica gel column chromatography (hexane:ethyl acetate=6:1to 2:1) to obtain an objective product (0.41 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.24 (3H, s), 2.85 (2H, t), 3.20 (2H, t),3.79 (2H, s), 4.18 (2H, q), 6.58 (1H, s), 7.48 (1H, s), 7.57 (2H, d),7.67 (2H, d).

Example 11(1) to Example 11(3)

In the same manner as in Example 11, cyclization was performed to obtainthe below-described compounds from the ketoamide forms and Lawson'sreagents.

Example 11(1) Ethyl4-methyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]acetate

An oily matter; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.24 (3H, s), 2.34 (3H,s), 2.82 (2H, t), 3.15 (2H, t), 3.69 (2H, s), 4.17 (2H, q), 6.59 (1H,s), 7.58 (2H, d), 7.66 (2H, d).

Example 11(2) Ethyl[4-isopropyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]acetate

An oily matter; ¹H-NMR (CDCl₃) δ 1.21-1.28 (9H, m), 2.21 (2H, s), 2.83(2H, t), 2.98-3.05 (1H, m), 3.20 (2H, d), 3.70 (2H, s), 4.16 (2H, q),6.58 (1H, s), 7.57 (2H, d), 7.66 (2H, d).

Example 11(3) Ethyl[4-methyl-2-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)-1,3-thiazol-5-yl]acetate

An oily matter; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.98-2.09 (2H, m), 2.28(3H, s), 2.33 (3H, s), 2.46 (2H, t), 2.94 (2H, t), 3.69 (2H, s), 4.18(2H, q), 6.59 (1H, s), 7.57 (2H, d), 7.67 (2H, d).

Example 12

Ethyl[2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]acetate

To a solution of ethyl4[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propanoyl)amino]-3-oxobutanoate(0.40 g) in N,N-dimethylformamide (5 ml) was added phosphorusoxychloride (0.13 ml) and the mixture was stirred at 70° C. for 1 hour.After standing to cool, a saturated sodium bicarbonate solution wasadded thereto, the mixture was diluted with ethyl acetate and washedwith water and saturated brine. The mixture was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=5:1 to 2:1) to obtain an objective product (0.30g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.26 (3H, t), 2.27 (3H, m), 2.83 (2H, t), 2.97 (2H, t),3.67 (2H, s), 4.16 (2H, q), 6.54 (1H, s), 6.85 (1H, s), 7.56 (2H, d),7.65 (2H, d).

Example 12(1) to Example 12(2)

In the same manner as in Example 12, cyclization was performed to obtainthe below-described compounds from the ketoamide forms and phosphorusoxychloride.

Example 12(1) Ethyl[4-methyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]acetate

An oily matter; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 2.10 (3H, s), 2.27 (3H,s), 2.79-2.84 (2H, m), 2.89-2.95 (2H, m), 3.60 (2H, s), 4.16 (2H, q),6.54 (1H, s), 7.56 (2H, d), 7.66 (2H, d).

Example 12(2) Ethyl[4-isopropyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]acetate

An oily matter; ¹H-NMR (CDCl₃) δ 1.20-1.27 (9H, m), 2.25 (3H, s),2.74-2.84 (3H, m), 2.88-2.98 (2H, m), 3.61 (2H, s), 4.15 (2H, q), 6.51(1H, s), 7.56 (2H, d), 7.65 (2H, d).

Example 13(1) to Example 13(7)

In the same manner as in Example 8, the ester forms obtained in Example11 and Example 12 were hydrolyzed to obtain the below-describedcompounds.

Example 13(1)[2-(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]aceticacid

Melting point 143-145° C.; ¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.83 (2H, t),3.21 (2H, t), 3.83 (2H, s), 6.55 (1H, s), 7.52 (1H, s), 7.56 (2H, d),7.65 (2H, d).

Example 13(2)[4-Methyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]aceticacid

Melting point 168-169° C.; ¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.34 (3H, s),2.79 (2H, t), 3.16 (2H, t), 3.72 (2H, s), 6.55 (1H, s), 7.54 (2H, d),7.64 (2H, d).

Example 13(3)[4-Isopropyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-thiazol-5-yl]aceticacid

Melting point 176-177° C.; ¹H-NMR (CDCl₃) δ 1.24 (3H, s), 1.26 (3H, s),2.20 (3H, s), 2.81 (2H, t), 2.99 (1H, quintet), 3.16 (2H, t), 3.75 (2H,s), 6.53 (1H, s), 7.56 (2H, d), 7.63 (2H, d).

Example 13(4)[4-Methyl-2-(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)-1,3-thiazol-5-yl]aceticacid

Melting point 162-163° C.; ¹H-NMR (CDCl₃) δ 1.96-2.07 (2H, m), 2.27 (3H,s), 2.33 (3H, s), 2.45 (2H, t), 2.97 (2H, t), 3.72 (2H, s), 6.58 (1H,s), 7.56 (2H, d), 7.66 (2H, d).

Example 13(5)[2-(2-{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]aceticacid

Melting point 143-144° C.; ¹H-NMR (CDCl₃) δ 2.24 (3H, s), 2.81 (2H, t),2.99 (2H, t), 3.71 (2H, d), 6.52 (1H, s), 6.90 (1H, s), 7.54 (2H, d),7.62 (2H, d).

Example 13(6)[4-Methyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]aceticacid

Melting point 120-121° C.; ¹H-NMR (CDCl₃) δ 2.09 (3H, s), 2.24 (3H, s),2.79 (2H, t), 2.93 (2H, t), 3.63 (2H, s), 6.51 (1H, s), 7.54 (2H, d),7.62 (2H, d).

Example 13(7)[4-Isopropyl-2-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)-1,3-oxazol-5-yl]aceticacid

Melting point 126-128° C.; ¹H-NMR (CDCl₃) δ 1.18 (3H, s), 1.21 (3H, s),2.26 (3H, s), 2.75-2.82 (3H, m), 2.95 (2H, t), 3.65 (2H, s), 6.47 (1H,s), 7.52 (2H, d), 7.61 (2H, d).

Example 14 2-(Trimethylsilyl)ethyl2-{[4-(3-methoxy-2-dimethyl-3-oxopropyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoate

To a solution of 2-(trimethylsilyl)ethyl2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (2.5 g) in ethylacetate (50 ml) was added 2,2′-azobis(isobutyronitrile) (0.11 g) andN-bromosuccinimide (1.20 g), and the mixture was heated under reflux for5 hours. The solvent was distilled off under reduced pressure and theresultant material was washed with toluene. Insolubles were filteredthrough Celite and washed with toluene. The solvent of the filtrate wasdistilled off under reduced pressure to obtain an oily matter. Theobtained oily matter was dissolved in N,N-dimethylformamide (50 ml).Potassium carbonate (1.40 g) and methyl3-(4-hydroxyphenyl)-2,2-dimethylpropanoate (1.55 g) were added and themixture was stirred at room temperature for 2 hours and at 50° C. for 1hour. The mixture was diluted with ethyl acetate, washed with water andsaturated brine and dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1to 10:1) to obtain an objective product (2.68 g) as an oily matter.

¹H-NMR (CDCl₃) δ 0.07 (9H, s), 1.07-1.11 (2H, m), 1.16 (6H, s), 2.79(2H, s), 3.64 (3H, s), 4.34-4.40 (2H, m), 5.39 (2H, s), 6.92 (2H, d),7.00-7.05 (3H, s), 7.63 (2H, d), 7.75 (2H, d).

Example 14(1) 2-(Trimethylsilyl)ethyl2-{[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoate

In the same manner as in Example 14, an objective product was obtainedfrom 2-(trimethylsilyl)ethyl2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate and ethyl2-(4-hydroxyphenoxy)-2-methylpropionate.

An oily matter ¹H-NMR (CDCl₃) δ 0.07 (9H, s), 1.05-1.14 (2H, m), 1.26(3H, dt), 1.54 (6H, s), 4.23 (2H, q), 4.33-4.42 (2H, m), 5.37 (2H, s),6.81-6.95 (4H, m), 7.05 (1H, s), 7.64 (2H, d), 7.76 (2H, d).

Example 152-{[4-(3-Methoxy-2,2-dimethyl-3-oxopropyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoicacid

To a solution of 2-(trimethylsilyl)ethyl2-{[4-(3-ethoxy-2,2-dimethyl-3-oxopropyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoate(2.65 g) in tetrahydrofuran (50 ml) was added tetra-n-butylammoniumchloride (a tetrahydrofuran solution (1 M), 5.7 ml) and the mixture wasstirred at room temperature overnight. The reactant was diluted withethyl acetate, washed with water and saturated brine and dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by recrystallization(hexane-ethyl acetate) to obtain an objective product (1.76 g) ascrystals.

Melting point 153-155° C.; ¹H-NMR (CDCl₃) δ 1.17 (6H, s), 2.80 (2H, s),3.65 (3H, s), 5.41 (1H, s), 6.94 (2H, d), 7.05 (2H, d), 7.11 (1H, s),7.65 (2H, d), 7.77 (2H, d).

Example 15(1)2-{[4-(2-Ethoxy-1,1-dimethyl-2-oxoethoxy)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoicacid

In the same manner as in Example 15, an objective product was obtainedfrom 2-(trimethylsilyl)ethyl2-{[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoateobtained in Example 14(1).

Melting point 87-88° C.; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.54 (6H, s),4.22 (2H, q), 5.38 (2H, s), 6.85 (2H, d), 6.92 (2H, d), 7.09 (1H, s),7.65 (2H, d), 7.77 (2H, d).

Example 16 Methyl3-[4-({3-(hydroxymethyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]-2,2-dimethylpropanoate

To a solution of2-{[4-(3-methoxy-2,2-dimethyl-3-oxopropyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoicacid (1.60 g) in tetrahydrofuran (40 ml) was sequentially added dropwisetriethylamine (0.58 ml) and ethyl chlorocarbonate (0.37 ml) withice-cooling, and then the mixture was stirred at room temperature for 30minutes. After cooling to −20° C., sodium borohydride (0.33 g) wasadded, and then methanol (20 ml) was added dropwise. The mixture wasstirred for 2 hours. The reaction was completed in 1 N hydrochloric acidand diluted with ethyl acetate. Then, the reactant was washed with waterand saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=5:1to 2:1) to obtain an objective product (1.16 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.17 (6H, s), 2.80 (2H, s), 3.63 (3H, s), 4.60 (2H, s),5.08 (2H, s), 6.82 (1H, s), 6.89 (2H, d), 7.04 (2H, d), 7.62 (2H, d),7.75 (2H, d).

Example 16(1) Ethyl2-[4-({3-(hydroxymethyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]-2-methylpropionate

In the same manner shown to Example 16, an objective product wasobtained from2-{[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furoicacid.

An oily matter; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.54 (6H, s), 4.24 (2H,q), 4.59 (2H, d), 5.05 (2H, s), 6.81 (1H, s), 6.86 (4H, d), 7.62 (2H,d), 7.75 (2H, d).

Example 173-[4-({3-(Hydroxymethyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]-2,2-dimethylpropanoicacid

In the same manner as in Example 8, the ester form obtained in Example16 was used to obtain an objective product.

Melting point 91-92° C.; ¹H-NMR (CDCl₃) δ 1.20 (6H, s), 2.82 (2H, s),4.56 (2H, s), 5.05 (2H, s), 6.76 (1H, s), 6.89 (2H, d), 7.10 (2H, d),7.59 (2H, d), 7.70 (2H, d).

Example 18 Methyl2,2-dimethyl-3-[4-({3-{[(phenoxycarbothioyl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]propionate

To a solution of methyl3-[4-({3-{[(hydroxymethyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]-2,2-dimethylpropionate(0.40 g) in acetonitrile (5 ml) was added 4-(dimethylamino)pyridine(0.211 g), and phenyl chlorothionoformate (0.132 ml) was added dropwisethereto with ice-cooling. The mixture was stirred with ice-cooling for30 minutes and at room temperature for 30 minutes. The reaction solutionwas diluted with ethyl acetate, washed with water, saturated brine anddried over anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=30:1 to 5:1) to obtain an objectiveproduct (0.40 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.17 (6H, s), 2.80 (2H, s), 3.64 (3H, s), 5.13 (2H, s),5.52 (2H, s), 6.89-6.92 (3H, m), 7.02-7.10 (3H, m), 7.19-7.33 (2H, m),7.37-7.47 (2H, m), 7.62 (2H, d), 7.76 (2H, d).

Example 18(1) Ethyl2-methyl-2-[4-({3-{[(phenoxycarbothioyl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]propionate

In the same manner as in Example 18, an objective product was obtainedfrom ethyl2-[4-({3-(hydroxymethyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]-2-methylpropionate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.54 (6H, s), 4.23 (2H,q), 5.11 (2H, s), 5.51 (2H, s), 6.87-6.91 (5H, m), 7.09 (2H, d), 7.31(1H, d), 7.38-7.45 (2H, m), 7.64 (2H, d), 7.77 (2H, d).

Example 19 Ethyl2,2-dimethyl-3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]propionate

To a solution of methyl2,2-dimethyl-3-[4-({3-{[(phenoxycarbothioyl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]propionate(0.40 g) in toluene (5 ml) was added 2,2′-azobis(isobutyronitrile)(0.022 g) and tributyltin hydride (0.27 ml) and the mixture was heatedunder reflux for 2 hours. The solvent was distilled off under reducedpressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=30:1 to 4:1) to obtain an objectiveproduct (0.17 g) as an oily matter.

¹H-NMR (CDCl₃) δ 1.17 (6H, s), 2.11 (3H, s), 2.80 (2H, s), 3.65 (3H, s),4.98 (2H, s), 6.62 (1H, s), 6.90 (2H, d), 7.04 (2H, d), 7.59 (2H, d),7.53 (2H, d).

Example 19(1) Ethyl2-methyl-2-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]propionate

In the same manner as in Example 19, an objective product was obtainedfrom2-methyl-2-[4-({3-{[(phenoxycarbothioyl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]propionate.

An oily matter; ¹H-NMR (CDCl₃) δ 1.27 (3H, t), 1.54 (6H, s), 2.09 (3H,s), 4.23 (2H, q), 4.95 (2H, s), 6.62 (1H, s), 6.86 (4H, d), 7.60 (2H,d), 7.73 (2H, d).

Example 20(1) and Example 20(2)

In the same manner as in Example 8, the ester forms obtained in Example19 and Example 19(1) were hydrolyzed to obtain the below-describedcompounds.

Example 20(1)2,2-Dimethyl-3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenyl]propionicacid

Melting point 124-126° C.; ¹H-NMR (CDCl₃) δ 1.20 (6H, s), 2.09 (3H, s),2.84 (2H, s), 4.97 (2H, s), 6.60 (1H, s), 6.91 (2H, d), 7.10 (2H, d),7.58 (2H, d), 7.71 (2H, d).

Example 20(2)2-Methyl-2-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]propionicacid

Melting point 116-117° C.; ¹H-NMR (CDCl₃) δ 1.55 (6H, s), 2.10 (3H, s),4.97 (2H, s), 6.61 (1H, s), 6.92 (4H, s), 7.59 (2H, d), 7.72 (2H, d).

Example 21-a Ethyl2-methyl-2-[4-((E)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionate

Example 21-b Ethyl2-methyl-2-[4-((Z)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionate

To a solution of 2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde(1.0 g) in N,N-dimethylformamide (20 ml) was added[4-(2-ethoxy-1,1-dimethyl-2-oxoethoxy)benzyl](triphenyl)phosphoniumbromide (2.66 g) and potassium carbonate (0.82 g) and the mixture wasstirred at room temperature overnight. The reaction solution was dilutedwith ethyl acetate, washed with water and saturated brine and dried overanhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=30:1 to 10:1) to obtain anobjective product (E-isomer; 0.53 g, Z-isomer; 0.54 g) as a solidmatter, respectively.

Ethyl2-methyl-2-[4-((E)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionate:

Melting point 99-100° C.; ¹H-NMR (CDCl₃) δ 1.26 (3H, t), 1.61 (6H, s),2.45 (3H, s), 4.24 (2H, q), 6.73 (2H, ABq), 6.82 (2H, d), 6.92 (1H, s),7.34 (2H, d), 7.60 (2H, d), 7.72 (2H, d).

Ethyl2-methyl-2-[4-((Z)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionate:

Melting point 84-85° C.; ¹H-NMR (CDCl₃) δ 1.24 (3H, t), 1.61 (6H, s),2.28 (3H, s), 4.22 (2H, q), 6.23 (1H, d), 6.42 (1H, s), 6.48 (1H, d),6.78 (2H, d), 7.20 (2H, d), 7.551 (2H, s), 7.558 (2H, s).

Example 22(1) and Example 22(2)

In the same manner as in Example 8, the ester forms obtained in Example21-a and Example 21-b were hydrolyzed to obtain the below-describedcompounds.

Example 22(1)2-Methyl-2-[4-((E)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionicacid

Melting point 140-141° C.; ¹H-NMR (CDCl₃) δ 1.63 (6H, s), 2.45 (3H, s),6.77 (2H, ABq), 6.92 (1H, s), 6.93 (2H, d), 7.39 (2H, d), 7.60 (2H, d),7.72 (2H, d).

Example 22(2)2-Methyl-2-[4-((Z)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionicacid

Melting point 117-118° C.; ¹H-NMR (CDCl₃) δ 1.61 (6H, s), 2.28 (3H, s),6.27 (1H, d), 6.41 (1H, s), 6.49 (1H, d), 7.87 (2H, d), 7.25 (2H, d),7.55 (4H, s).

Example 23 Ethyl2-methyl-2-[4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]propionate

To a solution of ethyl2-methyl-2-[4-((E)-2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethenyl)phenoxy]propionate(0.34 g) in a mixed solvent of toluene-ethanol (4 ml-1 ml) was addedchlorotris(triphenylphosphine) rhodium (I) (0.69 mg) and the mixture wasstirred at 60° C. under hydrogen atmosphere overnight. The solvent wasdistilled off under reduced pressure and diluted with diisopropyl ether.Insolubles were filtered and the filtrate was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1 to 5:1) to obtain an objectiveproduct (0.18 g) as a solid matter.

Melting point 99-100° C.; ¹H-NMR (CDCl₃) δ 1.25 (3H, t), 1.58 (6H, s),2.09 (3H, s), 2.62 (2H, t), 2.77 (2H, t), 4.23 (2H, q), 6.51 (1H, s),6.77 (2H, d), 7.00 (2H, d), 7.57 (2H, d), 7.66 (2H, d).

Example 242-Methyl-2-[4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]propionicacid

In the same manner shown to Example 8, an objective product was obtainedfrom ethyl2-methyl-2-[4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]propionate.

Melting point 87-88° C.; ¹H-NMR (CDCl₃) δ 1.51 (6H, s), 2.09 (3H, s),2.60 (2H, t), 2.76 (2H, t), 6.50 (1H, s), 6.84 (2H, d), 7.02 (2H, d),7.55 (2H, d), 7.62 (2H, d).

Example 252-Methyl-2-{4-({2-methyl-5-[4-trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}propionicacid

{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (0.35 g) anddi(4-(1-(ethoxycarbonyl)-1-methylethoxy)phenyl)disulfide (1.3 g) weredissolved in tetrahydrofuran (20 ml), tributylphosphine (1 ml) was addedthereto and the mixture was stirred at room temperature overnight. Thesolvent was distilled off and the residue was purified by basic silicagel column chromatography (ethyl acetate:hexane) and silica gel columnchromatography (ethyl acetate:hexane) to obtain oil (0.49 g). Theobtained oil was dissolved in ethanol (100 ml), a 1 N aqueous sodiumhydroxide solution (10 ml) was added and then the mixture was stirred atroom temperature overnight. After concentration, 1 N hydrochloric acidwas added and extracted with ethyl acetate. The organic layer was washedwith water and brine and dried over magnesium sulfate, and the solventwas distilled off to obtain crude crystals. The obtained crystals wererecrystallized from ethyl acetate-hexane to obtain an objective productas crystals.

Melting point 112-113° C.; ¹H-NMR (CDCl₃) δ 1.60 (6H, s), 2.07 (3H, s),3.80 (2H, s), 6.64 (1H, s), 6.85 (2H, d), 7.28 (2H, d), 7.58 (2H, d),7.67 (2H, d).

Example 262-Methyl-2-{4-[(3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propyl)thio]phenoxy}propionicacid

In the same manner as in Example 25, an objective product was obtainedfrom 3-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}propan-1-olobtained in Reference Example 11(1).

An oily matter; ¹H-NMR (CDCl₃) δ 1.59 (6H, s), 1.82-1.90 (2H, m), 2.29(3H, s), 2.50 (2H, t), 2.87 (2H, t), 6.53 (1H, s), 6.86 (2H, d), 7.27(2H, d), 7.57 (2H, d), 7.66 (2H, d).

Example 272-Methyl-2-{4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)amino]benzyl}thio)propionicacid

{2-Methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (0.7 g) wasdissolved in ethyl acetate (7 ml) and concentrated hydrochloric acid(0.73 ml) was added thereto with ice-cooling. The mixture was stirred atroom temperature for 1.5 hours. The mixture was poured into an aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with water and brine and dried over magnesiumsulfate, and the solvent was distilled off. The residue was dissolved inDMF (5 ml) and methyl 2-[(4-aminobenzyl)thio]-2-methylpropionate (0.5 g)and sodium hydrogen carbonate (0.5 g) were added. The reaction mixturewas heated at 60° C. for 2 hours. The mixture was poured into an aqueoussodium hydrogen carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with water and brine and dried over magnesiumsulfate, and the solvent was distilled off. The residue was purified bysilica gel column chromatography (dissolution medium: ethylacetate/hexane) to obtain an oily matter (0.4 g). The oily matter wasdissolved in ethanol (50 ml), a 1 N aqueous sodium hydroxide solution (5ml) was added thereto, and then the mixture was heated at 80° C. for 2.5hours. After concentration, a 1 N aqueous citric acid solution was addedand extracted with ethyl acetate. The organic layer was washed withwater and brine and dried over magnesium sulfate, and the solvent wasdistilled off to obtain crude crystals. The crude crystals wererecrystallized from ethyl acetate-hexane to obtain an objective product(0.33 g) as crystals.

Melting point 139-141° C.; ¹H-NMR (CDCl₃) δ 1.58 (6H, s), 2.37 (3H, s),3.82 (2H, s), 4.06 (2H, s), 6.60 (2H, d), 6.71 (1H, s), 7.16 (2H, d),7.58 (2H, d),7.68 (2H, d).

Formulation Example

Medicines comprising the compound of the present invention as an activeingredient can be prepared according to the following formulations.

Moreover, other ingredients (additives) than the active ingredient inthe following formulations, may be ones listed in JapanesePharmacopoeia, Japanese Standards for Pharmaceutical Ingredients orRegulations for Pharmaceutical Additives

-   1. Capsule

(1) 2-[(3-{[5-(4-fluorophenyl)-2-methyl-3- 10 mgfuryl]methoxy}benzyl)thiol]-2-methylpropionic acid (2) lactose 90 mg (3)microcrystalline cellulose 70 mg (4) magnesium stearate 10 mg 1 capsule180 mg (1), (2), (3) and ½ of (4) are mixed and then granulated. To thegranules is added the remainder of (4), and the whole is filled into agelatin capsule.

-   2. Capsule

(1) 3-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]- 10 mg3-furyl}methoxy)phenyl]propionic acid (2) lactose 90 mg (3)microcrystalline cellulose 70 mg (4) magnesium stearate 10 mg 1 capsule180 mg (1), (2), (3) and ½ of (4) are mixed and then granulated. To thegranules is added the remainder of (4), and the whole is filled into agelatin capsule.

-   3. Tablet

(1) 2-[(3-{[5-(4-fluorophenyl)-2-methyl-3- 10 mgfuryl]methoxy}benzyl)thio]-2-methylpropionic acid (2) lactose 35 mg (3)corn starch 150 mg  (4) microcrystalline cellulose 30 mg (5) magnesiumstearate  5 mg 1 tablet 230 mg (1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and then granulated. Tothe granules are added the remainders of (4) and (5), followed bysubjecting the mixture to compression molding, thereby giving a tablet.

-   4. Tablet

(1) 3-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]- 10 mg3-furyl}methoxy)phenyl]propionic acid (2) lactose 35 mg (3) corn starch150 mg  (4) microcrystalline cellulose 30 mg (5) magnesium stearate  5mg 1 tablet 230 mg (1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and then granulated. Tothe granules are added the remainders of (4) and (5), followed bysubjecting the mixture to compression molding, thereby giving a tablet.

-   5. Injection

(1) 2-[(3-{[5-(4-fluorophenyl)-2-methyl-3-  10 mgfuryl]methoxy}benzyl)thio]-2-methylpropionic acid (2) inositol 100 mg(3) benzyl alcohol  20 mg 1 ampoule 130 mg(1), (2) and (3) were dissolved in distilled water for injection to thetotal volume of 2 ml, and filled into an ampoule. All processes werecarried out under sterile conditions.

-   6. Injection

(1) 3-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-  10 mg3-furyl}methoxy)phenyl]propionic acid (2) inositol 100 mg (3) benzylalcohol  20 mg 1 ampoule 130 mg(1), (2) and (3) were dissolved in distilled water for injection to thetotal volume of 2 ml, and filled into an ampoule. All processes werecarried out under sterile conditions.

INDUSTRIAL APPLICABILITY

Compound (I) of the present invention and a pharmacologically acceptablesalt thereof show excellent preventing and treating action forPPAR-related diseases (e.g., lipid metabolism abnormality and sequelaethereof, diabetes mellitus, hyperlipidemia, arteriosclerotic disease andsequelae thereof (for example, ischemic cardiac disease, cerebraldisease, peripheral arterial occlusion and the like), impaired glucosetolerance and the like), by acting on PPAR. Therefore, Compound (I) ofthe present invention is useful as a PPAR controlling agent and aprophylactic or therapeutic agent for PPAR-related diseases (e.g., lipidmetabolism abnormality and sequelae thereof, diabetes mellitus,hyperlipidemia, arteriosclerotic diseases (for example, ischemic cardiacdisease, cerebral disease or peripheral arterial occlusion and thelike), impaired glucose tolerance and the like) in a mammal (e.g.,human, monkey, sheep, bovine, horse, dog, cat, rabbit, rat, mouse andthe like). Compound (I) of the present invention is also useful as anagent of raising high-density lipoprotein cholesterol, an agent oflowering triglyceride, an agent of lowering a low-density lipoproteincholesterol, an agent of suppressing progress of arteriosclerotic plaqueand the like. Furthermore, Compound (I) of the present invention hasregulating action for GPR40 receptor function, and is also useful as aninsulin secretion promoter or a prophylactic or therapeutic agent fordiabetes mellitus and the like.

1. A compound represented by the formula (I):

wherein R is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, p is 0, 1 or 2, and when p is2, each R may be the same or different, R¹ is a hydrogen atom or anoptionally substituted hydrocarbon group, R² is an optionallysubstituted aromatic group, Ring A is an optionally substituted benzene,X¹ is an oxygen atom or a sulfur atom, X² is an oxygen atom or—S(O)_(n)—, wherein n is 0, 1 or 2, Y is a bond, an oxygen atom,—S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)— and R³ is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, and m is 0, 1 or 2, M¹ and M² may be the same ordifferent and are each independently a bond or an optionally substituteddivalent aliphatic hydrocarbon group, M³ is an optionally substituteddivalent aliphatic hydrocarbon group and M⁴ is an optionally substituteddivalent aliphatic hydrocarbon group, or a pharmacologically acceptablesalt thereof, or a prodrug thereof, provided that (1) when Y is anoxygen atom or —S(O)_(m)—, M¹ is not a bond, and (2) when Y is a bondand one of M¹ and M² is a bond, the other of M¹ and M² is neither a bondnor methylene.
 2. The compound according to the claim 1, wherein R is anoptionally substituted alkyl, an optionally substituted aralkyl, anoptionally substituted cycloalkyl or an optionally substituted aryl. 3.The compound according to the claim 1, wherein p is
 1. 4. The compoundaccording to the claim 1, wherein R¹ is a hydrogen atom.
 5. The compoundaccording to the claim 1, wherein R² is an optionally substitutedphenyl.
 6. The compound according to the claim 1, wherein the formula:

is the formula:

wherein Ring A′ is an optionally further substituted benzene ring. 7.The compound according to the claim 1, wherein X¹ is an oxygen atom. 8.The compound according to the claim 1, wherein X² is an oxygen atom or asulfur atom.
 9. The compound according to the claim 1, wherein Y is anoxygen atom or a sulfur atom.
 10. The compound according to the claim 1,wherein Y is —C(═O)—N(R³)—, wherein R³ is a hydrogen atom, an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup, and the carbon atom is bonded to M¹, and the nitrogen atom to M².11. The compound according to the claim 10, wherein R³ is a hydrogenatom, an optionally substituted alkyl, an optionally substitutedaralkyl, an optionally substituted cycloalkyl or an optionallysubstituted aryl.
 12. The compound according to the claim 1, wherein M¹is an alkylene having 3 or more carbon atoms.
 13. The compound accordingto the claim 1, wherein M¹ and M² may be the same or different and areeach independently a bond, an alkylene, an alkenylene or an alkynylene,M³ is an alkylene, an alkenylene or an alkynylene, and M⁴ is analkylene, an alkenylene or an alkynylene.
 14. The compound according tothe claim 1, wherein the formula (I) is

wherein R is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R¹ is a hydrogen atom or anoptionally substituted hydrocarbon group, R² is an optionallysubstituted aromatic group, Ring A is an optionally substituted benzene,X¹ is an oxygen atom or a sulfur atom, X² is an oxygen atom or—S(O)_(n)—, wherein n is 0, 1 or 2, Y is a bond, an oxygen atom,—S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)— and R³ is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, and m is 0, 1 or 2, M¹ and M² may be the same ordifferent and are each independently a bond or an optionally substituteddivalent aliphatic hydrocarbon group, M³ is an optionally substituteddivalent aliphatic hydrocarbon group, and M⁴ is an optionallysubstituted divalent aliphatic hydrocarbon group, or a pharmacologicallyacceptable salt thereof, provided that (1) when Y is an oxygen atom or—S(O)_(m)—, M¹ is not a bond, and (2) when Y is a bond and one of M¹ andM² is a bond, the other of M¹ and M² is neither a bond nor methylene.15. The compound according to the claim 14, wherein the formula (I′) is

wherein R is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R¹ is a hydrogen atom or anoptionally substituted hydrocarbon group, R² is an optionallysubstituted aromatic group, Ring A′ is an optionally further substitutedbenzene ring, X¹ is an oxygen atom or a sulfur atom, X² is an oxygenatom or —S(O)_(n)—, wherein n is 0, 1 or 2, Y is a bond, an oxygen atom,—S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)— and R³ is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, and m is 0, 1 or 2, M¹ and M² may be the same ordifferent and are each independently a bond or an optionally substituteddivalent aliphatic hydrocarbon group, M³ is an optionally substituteddivalent aliphatic hydrocarbon group, and M⁴ is an optionallysubstituted divalent aliphatic hydrocarbon group, or a pharmacologicallyacceptable salt thereof, provided that (1) when Y is an oxygen atom or—S(O)_(m)—, M¹ is not a bond, and (2) when Y is a bond and one of M¹ andM² is a bond, the other of M¹ and M² is neither a bond nor methylene.16. The compound according to the claim 15, wherein X¹ is an oxygenatom, X² is an oxygen atom or —S(O)_(n)— wherein n is 0, 1 or 2, Y is anoxygen atom, M¹ is an optionally substituted C₁₋₃ alkylene, M² is abond, M³ is an optionally substituted methylene, and M⁴ is an optionallysubstituted methylene.
 17. The compound according to the claim 16,wherein M¹ and M³ may be the same or different and are eachindependently an optionally substituted methylene.
 18. The compoundaccording to the claim 14, wherein the formula (I′) is

wherein R is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R¹ is a hydrogen atom or anoptionally substituted hydrocarbon group, R² is an optionallysubstituted aromatic group, Ring A′ is an optionally further substitutedbenzene ring, X¹ is an oxygen atom or a sulfur atom, X² is an oxygenatom or —S(O)_(n)—, wherein n is 0, 1 or 2, Y is a bond, an oxygen atom,—S(O)_(m)—, —C(═O)—N(R³)— or —N(R³)—C(═O)— and R³ is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, and m is 0, 1 or 2, M^(1′) is an alkylene grouphaving 3 or more carbon atoms, M³ is a optionally substituted divalentaliphatic hydrocarbon group, and M⁴ is an optionally substituteddivalent aliphatic hydrocarbon group, or a pharmacologically acceptablesalt thereof, provided that (1) when Y is an oxygen atom or —S(O)_(m)—,M^(1′) is not a bond, and (2 when Y is a bond M¹ is neither a bond normethylene.
 19. The compound according to the claim 1, wherein R is anoptionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1, R¹is a hydrogen atom, R² is an optionally substituted phenyl group, Ring Ais an optionally substituted benzene ring, X¹ is an oxygen atom, X² isan oxygen atom, Y is an oxygen atom or —C(═O)—N(R³)— wherein R³ is ahydrogen atom, alkyl or aralkyl, and the carbon atom is bonded to M¹,and the nitrogen atom to M², M¹ and M² may be the same or different andare each independently a bond or alkylene, M³ is alkylene, and M⁴ isalkylene.
 20. The compound according to the claim 1, wherein R is anoptionally substituted alkyl, aryl or cycloalkyl group, p is 0 or 1, R¹is a hydrogen atom, R² is an optionally substituted phenyl group, Ring Ais an optionally substituted benzene ring, X¹ is an oxygen atom, X² is—S(O)_(n)—, wherein n is 0, 1 or 2, Y is an oxygen atom or—C(═O)—N(R³)—, wherein R³ is a hydrogen atom, alkyl or aralkyl, and thecarbon atom is bonded to M¹, and the nitrogen atom to M², M¹ and M² maybe the same or different and are each independently a bond or alkylene,M³ is alkylene, and M⁴ is alkylene.
 21. A pharmaceutical medicinecomposition comprising the compound according to the claim 1 or aprodrug thereof and a pharmaceutically acceptable carrier, excipient, ordiluent.
 22. An agent of regulating nuclear receptor PPAR comprising thecompound according to the claim 1 or a prodrug thereof.
 23. The agentaccording to the claim 22, which is a therapeutic agent for lipidmetabolism abnormality or sequelae thereof, arteriosclerotic disease orsequelae thereof, diabetes mellitus, or impaired glucose tolerance. 24.The medicine according to the claim 21, which is an agent of raisinghigh-density lipoprotein cholesterol, an agent of lowering triglyceride,an agent of lowering low-density lipoprotein cholesterol or an agent ofsuppressing progress of arteriosclerotic plaque.
 25. An agent ofregulating GPR40 receptor function comprising the compound according tothe claim 1 or a prodrug thereof.
 26. The agent according to claim 25,which is an agent of regulating insulin secretion, an agent of loweringblood glucose or an agent of protecting pancreatic β cells.
 27. Theagent according to claim 25, which is a therapeutic agent for diabetesmellitus, glucose intolerance, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis,obesity, hypoglycemia, insulin resistant syndrome, unstable diabetesmellitus, or insulin allergy.